Human papillomaviruses cause cervical cancer

HPV is the cause of virtually all cervical cancer. The health establishment has lied to the public for decades by deliberately using defective studies which failed to detect numerous HPV-positive cases. These studies exploit residual confounding in order to falsely blame smoking.

The International Agency for Research on Cancer, 1997

Volume 64, Human Papillomaviruses. Summary of Data Reported and Evaluation. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 1995. International Agency for Research on Cancer. Last updated 08/13/1997.

"5.5 Evaluation There is sufficient evidence in humans for the carcinogenicity of human papillomavirus (HPV) types 16 and 18. There is evidence suggesting lack of carcinogenicity to the cervix in humans of HPV types 6 and 11. There is limited evidence in humans for the carcinogenicity of some other HPV types. HPVs cannot infect animals. Some animal papillomaviruses cause cancer in their natural hosts."

"Overall Evaluation HPV types 16 and 18 are carcinogenic to humans (Group 1). HPV types 31 and 33 are probably carcinogenic to humans (Group 2A). Some HPV types other than 16, 18, 31 and 33 are possibly carcinogenic to humans (Group 2B). The carcinogenicity of types 16 and 18 is supported by experimental evidence that proteins of these viruses interfere with the functions of cellular regulatory pathways."

IARC Monograph 64 summary - Human papillomaviruses / International Agency for Research on Cancer (pdf, 6pp)
All Monographs / IARC

IARC, 2007

IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 90, Human Papillomaviruses, 2007. Page 468: "Strong epidemiological evidence confirmed the previous evaluation that HPV types 16 and 18 are carcinogenic to humans. The evidence for carcinogenicity was strongest for HPV 16. In addition, a convincing association, mainly from case–control studies, was found for HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66. HPV types 26, 68, 73 and 82 were associated with cervical cancer in some case–control studies but were rarely found in case series and were not associated with an increase in risk in prospective studies; overall, the epidemiological data for these types were not considered to show a consistent association. Despite a large amount of HPV type-specific data that failed to demonstrate an association, HPV 6 and 11 have been reported in very rare cases, but they did not contribute meaningfully to the burden of cervical cancer. Fewer data were available for other HPV types." (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Volume 90 (2007) Human Papillomaviruses. (Main page)). However, there is still no credible review of socioeconomic differences in exposure to HPV, and studies that are known to be deficient in detection of multiple infections and exposure from partners are still treated as credible evidence. Adjustments employed by some studies may have introduced spurious results, and there is no mention of the fact that confounding easily results from the high odds ratios of HPV infection (page 102.)

Volume 90, Human Papillomaviruses, 2007 / IARC

The fraud of IARC 2007: Page 7, "Co factors, Tobacco Smoking. Regardless of differences in the prevalence of current and past use of tobacco across the many studies and populations evaluated, tobacco smoking was consistently associated with risk for stage 3 cervical intraepithelial neoplasia and invasive squamous-cell carcinoma of the cervix. The risk estimates for this association were consistently in the range of 2.0 regardless of the study design (retrospective versus prospective), the restriction criteria employed (any HPV type-positive versus high-risk HPV-positive) and the covariates included in the model. Concordant with the vast amount of evidence that indicates that tobacco constituents are carcinogens and that smoking reduces immunological function, these data demonstrated that smoking is a co-factor with HPV in the development of invasive cervical cancer." (Summary of Data Reported and Evaluation

Summary of Data Reported and Evaluation, Volume 90, Human Papillomaviruses, 2007 / IARC

Confounding has NOT been ruled out because NO studies took into account the basic epidemiological principle that exposure to an infected partner matters. This is despite studies showing that the sexual behavior of men, through THEIR exposure to infected partners, increases the risks of cervical cancer in their female partners. For socioeconomic reasons, smokers are more likely to have been exposed.

The vaunted "vast amount of that indicates that tobacco constituents are carcinogens" is from animal models, which are irrelevant to a cancer in humans where a virus that is both necessary and sufficient, is involved in 99.7% of cases. And, of the laundry list of "tobacco-specific nitrosamines" IARC invokes, not one has been identified as a human carcinogen. (Molecular Mechanisms of HPV-Induced Carcinogenesis, p. 22.)

IARC claims that "As determined by the Ames Salmonella mutagenicity test, smokers are at an increased risk for having mutagenic cervical fluid (Holly et al., 1986)." (Molecular Mechanisms of HPV-Induced Carcinogenesis, p. 22.) This ignores the established fact that the Ames test is absolutely worthless as a measure of carcinogenicity, and is cynically designed to exploit public ignorance. IARC claims that "Cervical tissues from smokers have significantly elevated levels of DNA damage as measured by DNA adducts compared with nonsmokers (Simons et al., 1993, 1995; Melikian et al., 1999b)." But even in directly exposed lung tissue, BaP adduct levels of smokers and non-smokers overlap, and there is no evidence that these predict cancer in the first place. IARC claims that "Finally, tobacco smoke has been associated with aberrant hypermethylation of the tumour-suppressor gene p16 which significantly correlated with the grade of cervical disease (Lea et al., 2004)" This is because hypermethylation of p16 is solidly associated with the human papillomavirus itself, as well as other viruses, both carcinogenic and non-carcinogenic.

IARC claims that "In addition to its direct role in carcinogenesis, tobacco smoking has been associated with a generalized suppression of the immune system, including a significant decrease in NK cells and NK cell activity, in circulating levels of immunoglobulin (Ig)G and IgA (Ferson et al., 1979) and in Langerhans cells (Barton et al., 1988; Poppe et al., 1996). Langerhans cells are dendritic cells that are localized in the epithelium and present antigen to T lymphocytes. A reduction in the number of Langerhans cells available to detect and present viral antigens may facilitate the establishment and persistence of local viral infection. Giuliano et al. (2002c) demonstrated that tobacco smoking was associated with an increased risk for persistence and duration of high-risk HPV infection. The resultant viral persistence may increase the probability of the development of virally induced neoplastic transformation." (Molecular Mechanisms of HPV-Induced Carcinogenesis, p. 22.)

Molecular Mechanisms of HPV-Induced Carcinogenesis, Volume 90, Human Papillomaviruses, 2007 / IARC

Circulating levels of IgG and IgA merely reflect exposure to infections, while the claim of decreased NK cell function is smokers is based on a defective study that falsely blames smoking for an effect of cytomegalovirus infection. They are guilty of ignoring the fact that smokers are more likely to have been exposed to CMV, for socioeconomic reasons. And, IARC's use of a study from 1979 is proof of their malicious negligence in failing to update their information. The claim that "smoking reduces immunological function" employs studies that ignored the direct effect of HPV itself on cervical Langerhans cells.

IARC says that "When several epidemiological studies show little or no indication of an association between an exposure and cancer, the judgement may be made that, in the aggregate, they show evidence of lack of carcinogenicity. Such a judgement requires first of all that the studies giving rise to it meet, to a sufficient degree, the standards of design and analysis described above. Specifically, the possibility that bias, confounding or misclassification of exposure or outcome could explain the observed results should be considered and excluded with reasonable certainty." (Preamble. (d) Criteria for causality, pp. 10-11.)

Preamble, Volume 90, Human Papillomaviruses, 2007 / IARC

This should apply even more emphatically to studies which purport to find a risk, not just those that don't! Failure to do so is proof of using a biased double standard. The mathematical model by Phillips & Smith (1994) demonstrated that spurious odds ratios of 2.5 are easily generated by failing to identify exposures with ORs as low as 10. And confounding was confirmed by FX Bosch, who was a member of the IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2005.

List of Participants, Volume 90, Human Papillomaviruses, 2007 / IARC

The National Institutes of Health Consensus Statement, 1996

Cervical Cancer. NIH Consensus Statement 1996 April 1-3. "A strong causal relationship between HPV and cervical cancer and its precursors has been established. The evidence for this statement is as follows:

Evidently in order to make it acceptable to the powerful anti-smoking establishment, they listing smoking among "factors under investigation."

NIH HPV Consensus Statement / National Institutes of Health

(Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. JM Walboomers et al. J Pathol 1999 Sep;189(1):12-19). 866 cases minus 21 "that were qualitatively inadequate." "A recent report that 93 percent of invasive cervical cancers worldwide contain human papillomavirus (HPV) may be an underestimate, due to sample inadequacy or integration events affecting the HPV L1 gene, which is the target of the polymerase chain reaction (PCR)-based test which was used. The formerly HPV-negative cases from this study have therefore been reanalyzed for HPV serum antibodies and HPV DNA." On reanalysis of the specimens, HPV was found in most supposedly HPV-negative cases, and "the worldwide HPV prevalence in cervical carcinomas is 99.7 percent."

Walboomers - J Pathol 1999 abstract / PubMed

The causal relation between human papillomavirus and cervical cancer. FX Bosch, A Lorincz, N Muñoz, CJLM Meijer, KV Shah. J Clin Pathol 2002 Apr;55(4):244-265. Review. "The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide... This association has been evaluated under all proposed sets of causality criteria and endorsed by the scientific community and major review institutes. The finding is universally consistent, and to date there are no documented alternative hypotheses for the aetiology of cervical cancer." [The ritual invocations of "carcinogenic chemicals" notwithstanding. -cast] "The role of men as possible vectors of HPV was measured in the early epidemiological studies by questionnaires that asked about the sexual behaviour of the husbands or sexual partners of patients with cervical cancer and controls. In addition, more recent studies had the ability to measure HPV DNA in exfoliated cells from the penile shaft, the coronal sulcus, and the distal urethra. These and other studies consistently showed that the risk of cervical cancer for a given woman can be predicted by the sexual behaviour of her husband as much as her own sexual behaviour. In populations where female monogamy is dominant, the population of female sex workers plays an important role in the maintenance and transmission of HPV infections. Moreover, the probability that a woman is an HPV carrier and her risk of developing cervical cancer have been shown to be related to the presence of HPV DNA in the penis or the urethra of her husband or sexual partner." Then, these authors promptly forget this and lie that studies which simplistically compare HPV positive women are sufficient to demonstrate a supposed consistent risk from smoking, instead of that they reflect confounding by their failure to measure exposure from male partners. This consistent convenient forgetfulness is proof of conspiracy to falsely blame smoking. And, their reference to the Surgeon General is despicable, because the Surgeon General is not an esteemed scientist, but a politicized hack fronting for the corrupt, health fascist Lasker Lobby that has controlled the politicians and the health establishment for six decades.

Bosch et al. / J Clin Pathol 2002 full article
Bosch et al. / J Clin Pathol 2002 abstract

Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. X Castellsague, M Diaz, S de Sanjose, N Munoz, R Herrero, S Franceschi, RW Peeling, R Ashley, JS Smith, PJ Snijders, CJ Meijer, FX Bosch; International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. J Natl Cancer Inst 2006 Mar 1;98(5):303-315. "The adjusted overall odds ratio for cervical adenocarcinoma in HPV-positive women compared with HPV-negative women was 81.3 (95% CI = 42.0 to 157.1). HPV 16 and HPV 18 were the two most commonly detected HPV types in case patients and control subjects. These two types were present in 82% of the patients."

Castellsague / JNCI 2006 full article

As of July 27 and 31, 2006, only 58% of U.S. adults (70% of women and 47% of men) had heard of HPV. Of those who had, 70% supported the use of vaccine. (Seventy Percent of U.S. Adults Support Use of the Human Papillomavirus (HPV) Vaccine, According to New Wall Street Journal Online/Harris Interactive Health-Care Poll. Harris Interactive News Release, August 18, 2006.)

News Release, August 18, 2006 / Harris Interactive

Human papillomavirus genotypes and the cumulative 2-year risk of cervical precancer. CM Wheeler, WC Hunt, M Schiffman, PE Castle; Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study Group. J Infect Dis 2006 Nov 1;194(9):1291-1299. "The most common HPV genotypes detected at baseline, in descending order of prevalence, were 16, 52, 51, 31, 18, 53, 39, 56, 62, 59, and 58. When detected as a single-type HPV infection, HPV-16 had a 2-year cumulative risk of 50.6% (95% confidence interval [CI], 44.1%-57.2%) for > or =CIN2 and 39.1% (95% CI, 32.9%-45.7%) for > or =CIN3. For other singly detected carcinogenic HPV types, the risk of > or =CIN2 ranged from 4.7% (for HPV-59) to 29.5% (for HPV-31), and the risk of > or =CIN3 ranged from 0.0% (for HPV-59) to 14.8% (for HPV-31). Multiple infections with HPV genotypes of different risk classes resulted in a risk that was similar to, and not significantly different from, the risk observed for the HPV genotype of the highest risk class."

Wheeler - J Infect Dis 2006 abstract / PubMed

High human papillomavirus oncogene mRNA expression and not viral DNA load is associated with poor prognosis in cervical cancer patients. MA de Boer, ES Jordanova, CG Kenter, AA Peters, WE Corver, JB Trimbos, GJ Fleuren. Clin Cancer Res 2007 Jan 1;13(1):132-138. "We studied the number of viral DNA copies and the level of HPV E6/E7 mRNA expression in 75 HPV 16-positive or HPV 18-positive International Federation of Gynecology and Obstetrics stage Ib and IIa cervical cancer patients. Measurements were done with quantitative PCR. DNA copy number analysis was done on pure tumor cell samples enriched with flow sorting. mRNA expression data were compensated for the percentage of tumor cells included. RESULTS: The number of viral DNA copies was not predictive of survival in cervical cancer patients. In contrast, high HPV E6/E7 mRNA expression was strongly related to an unfavorable prognosis (P = 0.006). In a multivariate Cox model for overall survival, including all known prognostic variables and stratified for HPV type, the level of E6/E7 mRNA expression was an independent prognostic indicator, second only to lymph node status. No correlation was observed between DNA copy number and the level of HPV E6/E7 mRNA expression, which reflects that not all DNA copies are equally transcriptionally active." [Ordonez 2004 reported that Asian American strains of HPV16 E2 had less repression of E6/E7.]

de Boer - Clin Cancer Res 2007 abstract / PubMed

Abundance of multiple high-risk HPV infections in cervical cells analyzed by an ultra-sensitive HPV genotyping assay. M Schmitt, B Dondog, T Waterboer, M Pawlita, M Tommasino, T Gheit. J Clin Microbiol 2010 Jan;48(1):143-149. "In 735 selected cervical scrapes we compared HPV positivity determined by broad-spectrum BSGP5+/6+-PCR (BS) coupled to an established bead-based Multiplex HPV Genotyping (MPG) assay with that determined by a multiplex type-specific PCR (TS) coupled to a newly-developed MPG assay... The overall rate of HPV posititivity for the 19 types included in both assays was 60.9% and 72.2% with BS and TS, and multiple infections were found in 34.8% and 58.0%, respectively. In conclusion, the TS-PCR-MPG assay significantly increased the HPV DNA detection rate, the number of multiple infections and demonstrated that the prevalence of low copy HPV infections in the anogenital tract may be strongly underestimated using conventional HPV amplification methods, especially in multiple infections."

Schmitt - J Clin Microbiol 2010 abstract / PubMed

SGO: HPV Vaccine Stops Recurrence After Surgery. By Charles Bankhead. MedPage Today, Mar. 9, 2010. Re: Impact of the quadrivalent HPV 6/11/16/18 vaccine in women who hae undergone definitive therapy: Do these women benefit from vaccination? W Huh et al. Society of Gynecologic Oncologists 2010;Abstract LBA 3. 8,810 vaccinated women and 8,812 placebo controls. "Vaccinated women had more than a 40% reduction in the incidence of recurrence after surgery compared with women who had not been vaccinated." Author Warner Huh said, "We found that 66% of the HPV 6/11/16/18-related CIN cases in the placebo arm did not have the same type detected in the original definitive therapy specimen, suggesting disease from new infection... Vaccination of women who were negative to 14 HPV types at enrollment reduced the incidence of CIN 2+ associated with 10 nonvaccine HPV types by 32.5%. Disease prevented postsurgery might be due to protection against HPV types that are phylogenetically related to HPV 6/11/16/18."

HPV Vaccine Stops Recurrence After Surgery / MedPage Today 2010

Genotype-specific clearance of genital human papillomavirus infections among mothers in the Finnish Family HPV Study. K Louvanto, KJ Syrjänen, MA Rintala, SE Grénman, SM Syrjänen. J Clin Microbiol 2010 Aug;48(8):2665-2671. 131 of 252 women in the Finnish Family HPV Study cleared their infection during the prospective follow-up of 6 years. "HPV16 and multiple-type infections showed the lowest clearance among young mothers. Increasing age and negative oral HR HPV DNA status at baseline were associated with increased clearance, whereas a higher number of current sexual partners decreased the probability of species 7/9 HPV genotype clearance."

Louvanto / J Clin Microbiol 2010 abstract

The risk of cervical cancer associated with specific types of human papillomavirus: a case-control study in a UK population. NG Powell, SJ Hibbitts, AM Boyde, DG Newcombe, AJ Tristram, AN Fiander. Int J Cancer 2011 Apr 1;128(7):1676-1682. 262 cases, 8428 controls. Odds ratio for infection with HPV 16 was 2770 (95% CI 1050-7320); for HPV 18 was 950 (95% CI 330-2740). Other oncogenic types ranged from 20.2 to 386. "[I]nfection with a high-risk HPV in women older than 40 years was associated with an approximately 30-fold increased risk of invasive cervical cancer relative to women younger than 40 years."

Powell - Int J Cancer 2011 abstract / PubMed

Prevalence and type distribution of human papillomavirus in cervical adenocarcinoma in Korean women. JS Park, YT Kim, A Lee, Y Lee, D Jenkins, EC Pirog, AC Molijn, G Ramakrishnan, J Chen; EPI-HPV-030 Study Group. Gynecol Oncol 2013 Jul;130(1):115-120. "HPV DNA was detected in 90.3% (177/196) of CADC. HPV-18 was the most prevalent type (54.2%), followed by HPV-16 (44.1%) and HPV-45 (3.4%). Infection with any high-risk HPV type was identified in 97.7% of HPV-DNA-positive CADC. The biomarker p16 was positive in 92% of CADC cases and PR was positive in 19.6% of CADC."

Park - Gynecol Oncol 2013 abstract / PubMed

Are twenty human papillomavirus types causing cervical cancer? M Arbyn, M Tommasino, C Depuydt, J Dillner. J Pathol 2014 Dec;234(4):431-435. "In 2012, the International Agency for Research on Cancer concluded that there was consistent and sufficient epidemiological, experimental and mechanistic evidence of carcinogenicity to humans for twelve HPV types (HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58 and HPV59) for cervical cancer. Therefore these types were considered as 1A carcinogens. They all belong to the family of the alpha-papillomaviridae, in particular to the species α5 (HPV51), α-6 (HPV56), α-7 (HPV18, HPV39, HPV45, HPV59) and α - 9 (HPV16, HPV31, HPV35, HPV52, HPV58). Less evidence is available for a thirteenth type (HPV68, α-7), which is classified as a 2A carcinogen (probably carcinogenic). Moreover, seven other phylogenetically-related types (HPV26, HPV53, HPV66, HPV67, HPV68, HPV70 and HPV73) were identified as single HPV infections in certain rare cases of cervical cancer and were considered possibly carcinogenic (2B carcinogens). Recently, Halec et al demonstrated that the molecular signature of HPV-induced carcinogenesis (presence of type-specific spliced E6*| mRNA, increased expression of p16; and decreased expression of cyclin D1, p53 and Rb) was similar in cervical cancers containing single infections with one of the eight aforementioned 2A or 2B carcinogens as in cancers with single infections with group I carcinogens. Ninety six percent of cervical cancers are attributable to one of the thirteen most common HPV types (group I and IIa). Including the additional seven HPV types (group IIb) added 2.6% to reach a total of 98.7% of all HPV-positive cervical cancers. From recently updated meta-analyses, it was shown that HPV68, HPV26, HPV66, HPV67, HPV73 and HPV82 were significantly more common in cancer cases than in women with normal cervical cytology, suggesting that for these 6 HPV types an upgrading of the carcinogen classification could be considered. However, there is no need to include them in HPV screening tests or vaccines given their rarity."

Arbyn - J Pathol 2014 abstract / PubMed

Biological relevance of human papillomaviruses in vulvar cancer. G Halec, L Alemany, B Quiros, O Clavero, D Höfler, M Alejo, W Quint, M Pawlita, FX Bosch, S de Sanjose. Mod Pathol 2017 Apr;30(4):549-562. 447 cases. Viral transcripts were found in 87% of HPV DNA+ vulvar cancers, "resulting in an HPV-attributable fraction of at least 21% worldwide." 85% were HPV16, others were HPV26, 66, 67, 68, 70 and 73.

Halec - Mod Pathol 2017 abstract / PubMed

HPV prevalence in vulvar cancer in Austria. S Pils, L Gensthaler, L Alemany, R Horvat, S de Sanjosé, EA Joura. Wien Klin Wochenschr 2017 Nov;129(21-22):805-809. 41/177 consecutive samples tested positive for HPV DNA (23%). "The most commonly detected HPV strain was type 16, followed by 31 and 33."

Pils - Wien Klin Wochenschr 2017 full article / PubMed Central

Histological characteristics of HPV-associated and -independent squamous cell carcinomas of the vulva: A study of 1,594 cases. N Rakislova, O Clavero, L Alemany, A Saco, B Quirós, B Lloveras, M Alejo, M Pawlita, W Quint, M Del Pino, S de Sanjose, J Ordi; VVAP study group. Int J Cancer 2017 Dec 15;141(12):2517-2527. 441 out of 1,594 cases (27.7%) were HPV DNA+.

Rakislova - Int J Cancer 2017 abstract / PubMed

Sequencing detects human papillomavirus in some apparently HPV-negative invasive cervical cancers. LS Arroyo Mühr, C Lagheden, C Eklund, J Lei, S Nordqvist-Kleppe, P Sparén, K Sundström, J Dillner. J Gen Virol 2019 Dec 20 [Epub ahead of print]. "HPV was detected in 31/34 HPV PCR-positive cases. Among cases negative for HPV by PCR, 48/92 (52.2 %) contained HPV sequences, with HPV33 being the most commonly detected type among these (14/48 cases, 29.2 %)."

Arroyo Mühr - J Gen Virol 2019 abstract / PubMed

"The sexual behavior of men... can influence the risk of cervical cancer"

HPV in Men

Different strains in different populations

Enhanced oncogenicity of Asian-American human papillomavirus 16 is associated with impaired E2 repression of E6/E7 oncogene transcription. RM Ordonez, AM Espinosa, DJ Sanchez-Gonzalez, J Armendariz-Borunda, J Berumen. J Gen Virol 2004 Jun;85(Pt 6):1433-1444. "AA variants confer a nine times higher risk than E variants for cervical cancer... The low repression activity of E2 suggests that increased expression of E6/E7 oncogenes may occur much earlier in AA tumours. Therefore, the time period between viral infection and the emergence of a frankly invasive cancer may be decreased. This hypothesis could explain the association of the AA-c variant with patients 11 years younger than those with E variants (Berumen et al., 2001)." [de Boer 2007 reported decreased survival with increased expression of E6/E7 oncogenes.]

Ordonez - J Gen Virol 2004 full article

Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Clifford GM, Gallus S, Herrero R, Munoz N, Snijders PJ, Vaccarella S, Anh PT, Ferreccio C, Hieu NT, Matos E, Molano M, Rajkumar R, Ronco G, de Sanjose S, Shin HR, Sukvirach S, Thomas JO, Tunsakul S, Meijer CJ, Franceschi S; IARC HPV Prevalence Surveys Study Group. Lancet 2005 Sep 17-23;366(9490):991-998. "Women were randomly selected from the general population of 13 areas from 11 countries (Nigeria, India, Vietnam, Thailand, Korea, Colombia, Argentina, Chile, the Netherlands, Italy, and Spain)," total 15,613. "HPV prevalence varied nearly 20 times between populations, from 1.4% (95% CI 0.5-2.2) in Spain to 25.6% (22.4-28.8) in Nigeria. Although both overall HPV prevalence and HPV16 prevalence were highest in sub-Saharan Africa, HPV-positive women in Europe were significantly more likely to be infected with HPV16 than were those in sub-Saharan Africa (OR 2.64, p=0.0002), and were significantly less likely to be infected with high-risk HPV types other than HPV16 (OR 0.57, p=0.004) and/or low-risk HPV types (OR 0.44. p=0.0002). Women from South America had HPV-type distribution in between those from sub-Saharan Africa and Europe. Heterogeneity between areas of Asia was significant."

Clifford - Lancet 2005 abstract / PubMed

Prevalence of cervical human papillomavirus in Taiwanese women. CJ Jeng, Phdl, ML Ko, QD Ling, J Shen, HW Lin, CR Tzeng, CM Ho, TY Chien, SC Chen. Clin Invest Med 2005 Oct;28(5):261-266. "The overall HPV positivity was 19.85% and multiple infections were found in 35.84% of the infected group, 7.92% of the whole study population. The younger the subject, the higher was the infection rate and multiple infection rates. The most common HPV types were 16, 18, 58, 52, 51 and 56, which is different from the western world."

Jeng - Clin Invest Med 2005 abstract / PubMed

High prevalence of high-risk oncogenic human papillomaviruses harboring atypical distribution in women of childbearing age living in Libreville, Gabon. A Si-Mohamed, A Ndjoyi-Mbiguino, K Cuschieri, IN Onas, I Colombet, F Ozouaki, JL Goff, H Cubie, L Belec. J Med Virol 2005 Nov;77(3):430-438. "A total of 90 women (55%) harbored high-risk (HR) genotypes, with the most common being HPV-53 (19; 12%), HPV-58 (17; 11%), and HPV-16 (16; 10%). Low-risk genotypes were found in 36 (22%) women with HPV-54 and HPV-70 being the most frequently detected (17; 11% and 10; 6%, respectively). Finally 37 women (23%) tested positive for genotypes of unknown oncogenic risk, the most common in this category being HPV-83 (20; 12%). Multiple infections were detected in 35 (21%) women."

Si-Mohamed - J Med Virol 2005 abstract / PubMed

Oncogenic Human Papillomavirus (HPV) Type Distribution and HPV Type 16 E6 Variants in Two Spanish Population Groups with Different Levels of HPV Infection Risk. M Ortiz, M Torres, L Munoz, E Fernandez-Garcia, J Canals, AI Cabornero, E Aguilar, J Ballesteros, J del Amo, A Garcia-Saiz. J Clin Microbiol 2006 Apr;44(4):1428-1434. HPV types 16 and 31 were the most common in both sex workers/ imprisoned women and the general population, but the next most common strains differed between the two groups. Types 58, 66, 56, and 18 were the nest most frequent in the former group, and types 52, 68, 51, and 53 in the latter.

Ortiz et al. / J Clin Microbiol 2006 abstract

Human Papillomavirus Infections with Multiple Types and Risk of Cervical Neoplasia. H Trottier, S Mahmud, MC Costa, JP Sobrinho, E Duarte-Franco, TE. Rohan, A Ferenczy, LL Villa, EL Franco. Cancer Epidemiol Biomark Prevent 2006 Jul;15:1274-1280. "HSIL risk markedly increased with the number of types [odds ratio (OR), 41.5; 95% confidence interval (95% CI), 5.3-323.2 for single-type infections; OR, 91.7; 95% CI, 11.6-728.1 for two to three types; and OR, 424.0; 95% CI, 31.8-5651.8 for four to six types, relative to women consistently HPV-negative during the first year of follow-up]. The excess risks for multiple-type infections remained after exclusion of women infected with HPV-16, with high-risk HPV types, or persistent infections, particularly for any-grade SIL. Coinfections involving HPV-16 and HPV-58 seemed particularly prone to increase risk." And: Higher Risk for Cervical Cancer Seen Among Women Infected With Multiple HPV Types. DG News, July 10, 2006. Re Trottier et al, Cancer Epidemiology, Biomarkers & Prevention 2006 July. "'Women who harbor multiple infections are at higher risk for cervical lesions than those ever infected with one type only and should be followed more closely,' said Eduardo L. Franco, DrPH, leader of the study and professor of epidemiology and oncology, and director, division of cancer epidemiology at McGill University." "Both HPV 58 and 16 'seemed particularly prone to increase risk' for pre-cancerous lesions in the cervix, said Helen Trottier, PhD, the first author of the research paper." The most common types were 16, 53, 51, 31 and 18, with HPV 16 in 9 of single and 14% of multiple infections.

Trottier et al / Cancer Epidemiol Biomark Prev 2006 full article
Re Trottier et al - Cancer Epidemiol Biomark Prev 2006 / Doctors Guide

Comparison of DNA sequencing and Roche Linear array in human papillomavirus (HPV) genotyping. L Giuliani, A Coletti, K Syrjanen, C Favalli, M Ciotti. Anticancer Res 2006 Sep-Oct;26(5B):3939-3941. "The sequence analysis [by PCR] revealed the presence of 80 single high-risk types and 22 single low-risk types. With the Linear array, single infections were found in 46 cases, double infections in 37 cases, triple infections in 12 cases, and more than three in 6 cases. One case positive by sequencing gave a negative result by Linear array."

Giuliani - Anticancer Res 2006 abstract / PubMed

Sociodemographic factors associated with high-risk human papillomavirus infection. JA Kahn, D Lan, RS Kahn. Obstet Gynecol 2007 Jul;110(1):87-95. 1,921 women aged 14-59, data from NHANES. "High-risk HPV infection was present in 15.6% (95% confidence interval [CI] 12.6-18.6%) of participants, corresponding to a population prevalence of 12,028,293 U.S. women. Women living below the poverty line, compared with those living three or more times above it, were more likely to be positive for high-risk HPV (23% versus 12%, P = .03). Among participants living below the poverty line, only Mexican-American ethnicity (odds ratio [OR] 0.4, 95% CI 0.2-0.9) and unmarried status (OR 3.3, 95% CI 1.2-8.9) were associated with HPV prevalence. In contrast, several factors were associated with HPV among participants living above the poverty line, including black race (OR 1.4, 95% CI 1.0-2.0), income (OR 0.92, 95% CI 0.84-0.99), unmarried status (OR 2.0, 95% CI 1.3-3.0), and age (OR for 22-25 year olds 2.4, 95% CI 1.4-4.0). "

Kahn - Obstet Gynecol 2007 abstract / PubMed

Prevalence of human papillomavirus types 6, 11, 16, 18, 31, and 33 in a cohort of Greek women. E Panotopoulou, A Tserkezoglou, M Kouvousi, I Tsiaousi, G Chatzieleftheriou, D Daskalopoulou, G Magiakos. J Med Virol 2007 Dec;79(12):1898-1905. "HPV was detected in 62.9% of 256 ASCUS smears, 89.3% of 516 LSIL, 86.7% of 60 HSIL and 47.3% of 165 with cervical carcinoma. Overall, HPV 11 was the most common type (13.4%), followed by 18 (10.3%), 6 (7.2%), 16 (6.4%), 31 (3.4%) and 33 (3.4%). Multiple infections with two (11.3%) or more types, primarily 11 and 18 (4.8%), were also identified... Multiple infections were detected in 2.2% of normal and 31.7% of HSIL. HPV prevalence was 75.4% in abnormal and 24.6% in normal cervical smears. HPV 16 and 18 were the most common types in cancer. Single infection with type 11 and multiple infections with 11 and 18 were more frequent."

Panotopoulou - J Med Virol 2007 abstract / PubMed

Homogeneous Amplification of Genital Human Alpha Papillomaviruses by Novel Broad Spectrum BSGP5+/6+ PCR. M Schmitt, B Dondog, T Waterboer, M Pawlita. J Clin Microbiol 2008 Mar;46(3):1050-9. New broad-spectrum (BS) primers improve detection of 14 genital HPV types and add 5 probes for low-risk types. "BSGP5+/6+ was significantly more sensitive than GP5+/6+ for detection of HPV 30,39,42,44,51,52,53,68,73 and 82, detecting 212 additional HPV infections and increasing the proportion of multiple infections from 17.2 to 26.9% in cancer patients."

Schmitt / J Clin Microbiol 2008 full article
Schmitt - J Clin Microbiol 2008 full article / PubMed Central

Evaluation of Different Techniques for Identification of Human Papillomavirus Types of Low Prevalence. I Sabol, M Salakova, J Smahelova, M Pawlita, M Schmitt, NM Gasperov, M Grce, R Tachezy. J Clin Microbiol 2008 May;46(5):1606-1613. "Interassay agreement was moderate in cases of single HPV infections and poor in cases of multiple HPV infections. The LA [Roche Diagnostics linear array] and the BS-based RLB [broad spectrum noncommercial reverse line blot] assays found a higher rate of cases positive for multiple HPV types than LiPA [Innogenetics INNO-LiPA (line probe assay)] and the GP-based RLB assay. The weakest capability in detecting multiple HPV infections was observed for LiPA."

Sabol / J Clin Microbiol 2008 abstract

Comparison of GP5ᆵPCR and SPF10-Line Blot Assays for Detection of High-Risk Human Papillomavirus in Samples from Women with Normal Cytology Results Who Develop Grade 3 Cervical Intraepithelial Neoplasia. AT Hesselink, MAPC van Ham, DAM Heideman, ZMA Groothuismink, L Rozendaal, J Berkhof, FJ van Kemenade, LAFG Massuger, WJG Melchers, CJLM Meijer, PJF Snijders. J Clin Microbiol 2008 Oct;46(10):3215-3221. SPF10 scored significantly more controls as hrHPV positive than did GP5ᆵPCR; "Consequently, women with normal cytology results and an hrHPV GP5ᆵPCR-positive test exhibited a risk of CIN 3 that was 4.5 times higher (odds ratio [OR], 65; 95% confidence interval [95%CI], 24 to 178) than that seen for women with an hrHPV-positive SPF10 test (OR, 14; 95%CI, 5 to 38))... Our data indicate that GP5ᆵPCR has a better clinical performance than SPF10 for women who are diagnosed with CIN 3 after prior normal cytology results. The extra positivity scored by SPF10 mainly involved infections characterized by low viral loads that do not result in CIN 3."

Hesselink / J Clin Microbiol 2008 abstract

Upstream Regulatory Region Alterations Found in HPV-16 Isolates from Cervical Carcinomas Increase Transcription, ori Function and HPV Immortalization Capacity in Culture. MJ Lace, C Isacson, JR Anson, AT Lörincz, SP Wilczynski, TH Haugen, LP Turek. J Virol 2009 Aug;83(15):7457-7466. "A subset of the altered URRs increased the potential of HPV-16 to establish persistent, cell growth-altering viral genome replication in the cell. This aggressive phenotype in culture was not solely due to increased viral early gene transcription but also to augmented initial amplification of the viral genome... The nucleotide sequence changes correlate with those previously described in the distinct, geographical North American type 1 (NA1) and Asian-American (AA) variants that are associated with more aggressive disease in epidemiologic studies and encompass, but are not limited to, alterations in previously characterized sites for the negative regulatory protein YY1."

Lace - J Virol 2009 abstract / PubMed

Human papillomavirus genotyping in archival vulval dysplastic or neoplastic biopsy tissues: comparison between the INNO-LiPA and Linear Array assays. SE Tan, SM Garland, AR Rumbold, SN Tabrizi. J Clin Microbiol 2010 Apr;48(4):1458-1460. "Roche Linear Array (LA) and Innogenetics INNO-LiPA HPV genotyping assays were compared on paraffin-embedded vulval tissues. LA detected amplifiable DNA in 28 (57%) out of 49 biopsies, 20 (40%) being HPV genotyped, compared to 49 (100%) and 41 (83%) respectively by INNO-LiPA."

Tan - J Clin Microbiol 2010 abstract / PubMed

Human papillomavirus type 58: the unique role in cervical cancers in East Asia. PK Chan. Cell Biosci 2012 May 9;2(1):17. Review. "A high prevalence of HPV58 among squamous cell carcinoma has been reported from China (28% in Shanghai, 10% in Hong Kong and 10% in Taiwan) and other countries in East Asia including Korea (16%) and Japan (8%). HPV58 ranks the third in Asia overall, but contributes to only 3.3% of cervical cancers globally. The reasons for a difference in disease attribution may lie on the host as well as the virus itself. HLA-DQB1*06 was found to associate with a higher risk of developing HPV58-positive cervical neoplasia in Hong Kong women, but not neoplasia caused by other HPV types. An HPV58 variant (E7 T20I, G63S) commonly detected in Hong Kong was found to confer a 6.9-fold higher risk of developing cervical cancer compared to other variants."

Chan - Cell Biosci 2012 full article / PubMed Central
Chan / Cell Biosci 2012 full article

Gene expression profiles induced by E6 from non-European HPV18 variants reveals a differential activation on cellular processes driving to carcinogenesis. V Fragoso-Ontiveros, R María Alvarez-García, A Contreras-Paredes, F Vaca-Paniagua, L Alonso Herrera, C López-Camarillo, N Jacobo-Herrera, M Lizano-Soberón, C Pérez-Plasencia. Virology 2012 Oct 10;432(1):81-90. "Our results show that E6 derived from non-European variants are able to up-regulate cellular transcripts associated to the hallmarks of cancer; such as cell cycle, migration, Wnt pathway and mTor signaling. Moreover, we were able to show that HPV18 E6 from African variant had a major effect on cellular processes such as cell cycle and migration as confirmed by functional studies."

Fragoso-Ontiveros - Virology 2012 abstract / PubMed

The Asian-American E6 variant protein of human papillomavirus 16 alone is sufficient to promote immortalization, transformation and migration of primary human foreskin keratinocytes. S Niccoli, S Abraham, C Richard, I Zehbe. J Virol 2012 Nov;86(22):12384-12396. "The ability to immortalize and transform primary human foreskin keratinocytes (PHFKs) to acquire resilient phenotypes and the ability to promote cell migration were evaluated. The immortalization capability was assayed based on population doublings, number of passages, surpassing mortality stage 1 and 2, hTERT expression and the ability to overcome G1 arrest via p53 degradation. Transformation and migration efficiency were analyzed using a combination of functional cell-based assays. We observed that either AAE6 or prototype E6 proteins alone were sufficient to immortalize PHFKs, albeit the AAE6 was more potent in doing so. The AAE6 variant protein alone pushed PHFKs through transformation and significantly increased their migration ability over that of the E6 prototype."

Niccoli - J Virol 2012 abstract / PubMed

Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations. PK Chan, C Zhang, JS Park, KK Smith-McCune, JM Palefsky, L Giovannelli, F Coutlée, S Hibbitts, R Konno, W Settheetham-Ishida, TY Chu, A Ferrera, M Alejandra Picconi, F De Marco, YL Woo, T Raiol, P Piña-Sánchez, JH Bae, MC Wong, MZ Chirenje, T Magure, AB Moscicki, AN Fiander, G Capra, E Young Ki, Y Tan, Z Chen, RD Burk, MC Chan, TH Cheung, D Pim, L Banks. Int J Cancer 2013 Jun 1;132(11):2528-2536. "The frequency of sequence variation varied geographically. Africa had significantly more isolates with E6-367A (D86E) but significantly less isolates with E6-203G, -245G, -367C (prototype-like) than other regions (p ≤ 0.003). E7-632T, -760A (T20I, G63S) was more frequently found in Asia, and E7-793G (T74A) was more frequent in Africa (p < 0.001). Variants with T20I and G63S substitutions at E7 conferred a significantly higher risk for cervical intraepithelial neoplasia grade III and invasive cervical cancer compared to other HPV58 variants (odds ratio = 4.44, p = 0.007)."

Chan - Int J Cancer 2013 abstract / PubMed

Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer. AA Chen, DA Heideman, D Boon, Z Chen, RD Burk, H De Vuyst, T Gheit, PJ Snijders, M Tommasino, S Franceschi, GM Clifford. Virology 2014 Jan 5;448:356-362. E6 and E7 variants in 213 HPV33-positive cervical samples from 30 countries. "We identified 28 HPV33 variants that formed 5 phylogenetic groups: the previously identified A1, A2, and B (sub)lineages and the novel A3 and C (sub)lineages. The A1 sublineage was strongly over-represented in cervical cases compared to controls in both Africa and Europe."

Chen - Virology 2014 abstract / PubMed

Human papillomavirus 16 non-European variants are preferentially associated with high-grade cervical lesions. LB Freitas, Z Chen, EF Muqui, NA Boldrini, AE Miranda, LC Spano, RD Burk. PLoS One 2014 Jul 1;9(7):e100746. 281 specimens. "Classification of disease into CIN3+ vs. <CIN3 indicated that NE types were associated with high-grade disease with an OR = 4.6 (1.07-20.2, p = 0.05)."

Freitas - PLoS One 2014 full article / PubMed Central
Freitas / PLoS One 2014 full article

Specificity of the Linear Array HPV Genotyping Test for detecting human papillomavirus genotype 52 (HPV-52). A Oštrbenk, BJ Kocjan, M Poljak. Acta Dermatovenerol Alp Pannonica Adriat 2014 Sep;23(3):53-56. "The most widely used HPV genotyping assay, the Roche Linear Array HPV Genotyping Test (Linear Array), is unable to identify HPV-52 status in samples containing HPV-33, HPV-35, and/or HPV-58... The HPV-52-specific assay detected HPV-52 in all 100 samples reactive with the Linear Array HPV-33/35/52/58 cross-reactive probe, but not with the HPV-33, HPV-35, and/or HPV-58 probes."

Oštrbenk / Acta Dermatovenerol Alp Pannonica Adriat 2014 full article (pdf, 4 pp)

Genetic Variations of Human Papillomavirus Type 16: Implications for Cervical Carcinogenesis. I Kukimoto, M Muramatsu. Jpn J Infect Dis 2015 Mar 13;68(3):169-175. Review. "Recent progress in determining HPV genomic sequences from clinical samples has revealed a wide variety of HPV16 genome sequences, and has allowed the comprehensive classification of intratype HPV16 variants. These consist of four variant lineages containing nucleotide variations in 1.0-10.0% of the complete viral genome sequences. Epidemiological data suggest that the non-European-Asian lineages of HPV16 entail a higher risk of progression to invasive cervical cancer than the European-Asian lineage."

Kukimoto & Muramatsu / Jpn J Infect Dis 2015 full article landing

Human papillomavirus 58E7 T20I/G63S variant isolated from an East Asian population possesses high oncogenicity. SS Boon, C Xia, JY Lim, Z Chen, PTY Law, ACM Yeung, M Thomas, L Banks, PKS Chan. J Virol 2020 Jan 29 [Epub ahead of print]. Type 58 is the third most commonly detected HPV type in cervical cancer among Eastern Asians. Natural variant T20I/G63S "possesses a greater ability to immortalise and transform primary cells, as well as degrading pRB more effectively than the prototype and other common variants."

Boon - J Virol 2020 abstract / PubMed

HPV-Associated Cancers and Socioeconomic Class


For cervical cancer, "About 10 out of every 100,000 women who live in counties in which fewer than 10% of residents have an income below the federal poverty level are diagnosed with cervical cancer each year. The rate climbs to about 13 women per 100,000 in counties in which 10% to less than 20% of residents are below poverty level, and peaks at about 19 per 100,000 [women] in poorer counties." For penile cancer, "About 1 out of every 100,000 men who live in counties in which fewer than 10% of residents have an income below the federal poverty level is diagnosed with penile cancer each year. The rate climbs to about 1.3 men per 100,000 in counties in which 10% to less than 20% of residents are below poverty level, and peaks at about 1.6 per 100,000 men in poorer counties." (HPV-Associated Cancers and Poverty Levels, Centers for Disease Control and Prevention. Page last updated: November 5, 2008. Page removed

The prevalence of the human papillomavirus in cervix and vagina in low-risk and high-risk populations. M Baay, V Verhoeven, K Wouters, F Lardon, P Van Damme, D Avonts, E Van Marck, P Van Royen, JB Vermorken. Scand J Infect Dis 2004;36(6-7):456-459. In 96 women visiting their general practitioner, and 63 sex workers visiting a STI clinic, "The overall HPV prevalence was 22.8%; 14.3% in the general population (14.3% in the cervix, 11.9% in the vagina), compared with 34.4% in sex workers (31.1% in the cervix, 27.9% in the vagina)."

Baay - Scand J Infect Dis 2004 abstract / PubMed

Multicenter study of knowledge about human papilloma virus and attitudes among emergency department patients. JC Millen, AA Ginde, AT Anderson, P Fang, CA Camargo Jr. J Pediatr Adolesc Gynecol 2009 Dec;22(6):356-359. Of 387 patients in Massachusetts, 242 (63%) had heard of HPV. Patients who were older, poorer or black were less likely to have heard of it. "Of those people who had heard of HPV, 82% knew of its relationship to cervical cancer, but only 61% thought it was a sexually transmitted disease (STD)."

Millen - J Pediatr Adolesc Gynecol 2009 abstract / PubMed

Factors associated with genital human papillomavirus infection among adult females in the United States, NHANES 2007-2010. R Shi, S Devarakonda, L Liu, H Taylor, G Mills. BMC Res Notes 2014 Aug 18;7:544. 4242 cervical swabs of females age 18-59. "The weighted prevalence of HPV infection was 41.9%. An estimated 59.4% of non-Hispanic black females had HPV infection... HPV infection was 5.77 times more likely for women with >11 sexual partners compared to women with 0-1 partners. Non-Hispanic black females were 1.87 times more likely to have HPV infection compared to non-Hispanic white females. Participants with only a high school degree had a 58% increased prevalence compared to college-educated women. Uninsured women had a 39% increased prevalence compared to those with insurance."

Shi - BMC Res Notes 2014 full article / PubMed Central
Shi / BMC Res Notes 2014 full article

Cervical Cancer Incidence in Ontario Women: Differing Sociodemographic Gradients by Morphologic Type (Adenocarcinoma Versus Squamous Cell). MV Prummel, SW Young, E Candido, D Nishri, L Elit, LD Marrett. Int J Gynecol Cancer 2014 Sep;24(7):1341-1346. Incident cancers 1991-2009 from the Ontario Cancer Registry. "Incidence was 51% higher in the poorest neighborhoods compared with the richest (RR, 1.51; 95% CI, 1.42-1.61) and 7% higher in rural areas compared with urban (RR, 1.07; 95% CI, 1.01-1.13). Incidence of squamous cell carcinoma was significantly higher in the poorest neighborhoods compared with the richest (RR, 1.74; 95% CI, 1.61-1.88), a trend observed for all time periods, and in rural areas compared with urban (RR, 1.10; 95% CI, 1.02-1.18). For adenocarcinoma, ASIRs in the earlier time period (1991-1998) were higher in the poorest neighborhoods compared with richest (RR, 1.26; 95% CI, 1.01-1.57), whereas for the more recent time period (1999-2009), ASIRs were lower for women living in the poorest neighborhoods compared with the richest (RR, 0.82; 95% CI, 0.68-0.99)."

Prummel - Int J Gynecol Cancer 2014 abstract / PubMed

Assortative mixing as a source of bias in epidemiological studies of sexually transmitted infections: the case of smoking and human papillomavirus. P Lemieux-Mellouki, M Drolet, J Brisson, EL Franco, MC Boily, I Baussano, M Brisson. Epidemiol Infect 2016 May;144(7):1490-1499. Mathematical model with nested cross-sectional study on the smoking-HPV association. The probability of selecting a highly sexually active partner is greater for smokers; thus, "The assortativity bias caused an overestimation of the odds ratio (OR) in the simulated study after perfect adjustment for the subjects' individual-level characteristics (adjusted OR 1·51 instead of 1·00)."

Lemieux-Mellouki - Epidemiol Infect 2016 abstract / PubMed

Human Papillomavirus Prevalence Is Associated With Socioeconomic Gradients Within a Medically Underserved Appalachian Region. SL Ware, R Crosby, R Fisher, ME Hagensee. Sex Transm Dis 2017 Dec;44(12):750-755. "Prevalence was 55.6%, with 33% having at least 1 high-risk infection. Prevalence was 27.8% for 9-valent HPV vaccine-preventable types and 39.2% for multiple types. Compared with FPL for a family of 4, women with federal poverty level for 1 person had 3 times greater prevalence, 2.3 times greater prevalence of high-risk types, and 2.5 times greater prevalence of multiple types."

Ware - Sex Transm Dis 2017 abstract / PubMed


HPV is Both a Necessary and a Sufficient Cause of Cervical Cancer

The human papillomavirus type 16 E6 gene alone is sufficient to induce carcinomas in transgenic animals. S Song, HC Pitot, PF Lambert. J Virol 1999 Jul;73(7):5887-5893. "We generated K14E6 transgenic mice in which the HPV16 E6 gene was expressed in the basal layer of epithelia, using the hK14 promoter. Expression of E6 increased cell proliferation and induced epidermal hyperplasia. Skin tumors developed in adult K14E6 mice with an incidence of about 7% at 1 year of age. In contrast to the tumors derived from K14E7 transgenic mice, which were primarily benign, tumors derived from K14E6 transgenic mice were mostly malignant, indicating that E6 alone not only is sufficient to induce tumors but may contribute to the development of malignancy in animals." "Inactivation of p53, however, may not be the only mechanism for E6-induced carcinogenesis. The K14E6 mice that developed tumors also displayed hyperplastic changes in the epidermis, a property that, as discussed above, cannot be ascribed to E6's inactivation of p53. It is likely that the hyperproliferation induced by E6 is important for its carcinogenesis. Another activity that may contribute to E6-associated carcinogenesis is its apparent inhibition of cellular differentiation. Cancer cells usually lack the ability to terminally differentiate. In this study, we found that the suprabasal compartment of the K14E6 transgenic epidermis stained for K14, indicating that E6 may also perturb cellular differentiation; this perturbation was caused by p53-independent activities of E6."

Song / J Virol 1999 full article

Inactivation of RAS association domain family 1A gene in cervical carcinomas and the role of human papillomavirus infection. I Kuzmin, L Liu, R Dammann, L Geil, EJ Stanbridge, SP Wilczynski, MI Lerman, GP Pfeifer. Cancer Res 2003 Apr 15;63(8):1888-1893. "The RASSF1A promoter is hypermethylated in 4 of 42 (= 10%) of squamous cell carcinomas, in 4 of 19 (= 21%) of adenosquamous carcinomas, and in 8 of 34 (= 24%) of cervical adenocarcinomas. Although in adenocarcinomas, methylation of RASSF1A and presence of human papillomavirus (HPV) type 16 or 18 sometimes coexisted, not a single case of HPV-16/18-positive squamous cell carcinomas had RASSF1A methylation." There was "a borderline-significant reverse correlation between inactivation of RASSF1A and the presence of high-risk HPVs. Our data imply that the presence of HPVs in cervical carcinomas alleviates the requirement for RASSF1A inactivation and suggests that these two events may engage the same tumorigenic pathway."

Kuzmin - Cancer Res 2003 abstract / PubMed

p53-independent abrogation of a postmitotic checkpoint contributes to human papillomavirus E6-induced polyploidy. Y Liu, SA Heilman, D Illanes, G Sluder, JJ Chen. Cancer Res 2007 Mar 15;67(6):2603-2610. "We found that E6 expression does not affect the spindle checkpoint. Instead, we provide direct evidence that E6 is capable of abrogating the subsequent G(1) arrest after adaptation of the mitotic stress. E6 targets p53 for degradation, and previous studies have shown an important role for p53 in modulation of the G(1) arrest after mitotic stress. Importantly, we have discovered that E6 mutants defective in p53 degradation also induce polyploidy, although with lower efficiency. These results suggest that E6 is able to induce polyploidy via both p53-dependent and p53-independent mechanisms... Polyploidy is often an early event during cervical carcinogenesis, and it predisposes cells to aneuploidy, which is thought to play a causal role in tumorigenesis."

Liu - Cancer Res 2007 abstract / PubMed
Liu / Cancer Res 2007 full article

Association between hTERT activation by HPV E6 proteins and oncogenic risk. K Van Doorslaer, RD Burk. Virology 2012 Nov 10;433(1):216-219. "Expression of activated telomerase and subversion of the p16/pRb pathway is sufficient and essential for the in vitro immortalization of primary keratinocytes... We used a luciferase-based assay to test the ability of 29 viral types, representing all current species within the Alphapapillomavirus genus, to activate the hTERT promoter. We show that oncogenic types specifically activate the hTERT promoter, while non-oncogenic types do not."

Van Doorslaer - Virology 2012 abstract / PubMed

Genomic amplification of the human telomerase gene (hTERC) associated with human papillomavirus is related to the progression of uterine cervical dysplasia to invasive cancer. H Liu, S Liu, H Wang, X Xie, X Chen, X Zhang, Y Zhang. Diagn Pathol 2012 Oct 30;7:147. 114 patients with non neoplastic lesion and 21 with cervical cancer, 53 analyzed for telomerase activity. "The positive correlation was found between the level of hTERC amplification and histologic grading of dysplasia (CIN2/3 from CIN1 or normal, P=0.03). A profounding increase in the accumulation of HPV and hTERC positive cases was observed in the CIN3 subgroup compared with the CIN2 group, 25% versus 62.96%, respectively (p=0.007)."

Liu / Diagn Pathol 2012 full articleLiu - Diagn Pathol 2012 full article / PubMed Central

Methylation of HPV18, HPV31, and HPV45 Genomes and Cervical Intraepithelial Neoplasia Grade 3. N Wentzensen, C Sun, A Ghosh, W Kinney, L Mirabello, S Wacholder, R Shaber, B Lamere, M Clarke, AT Lorincz, PE Castle, M Schiffman, RD Burk. J Natl Cancer Inst 2012 Nov 21;104(22):1738-1749. "We recently demonstrated that the HPV16 genome is strongly methylated in cervical precancer compared with transient infections... For all three HPV types, we observed strongly elevated methylation levels at multiple CpG sites in the E2, L2, and L1 regions among women with cervical intraepithelial neoplasia grade 3 compared with women with transient infections. We observed high correlation of methylation patterns between phylogenetically related types. The highest areas under the curve were 0.81 for HPV31, 0.85 for HPV18, and 0.98 for HPV45. Differential methylation patterns in cervical intraepithelial neoplasia grade 3 patients with multiple infections suggest that methylation can clarify which of the infections is causal. Conclusions Carcinogenic HPV DNA methylation indicates transforming HPV infections."

Wentzensen - J Natl Cancer Inst 2012 abstract / PubMed

Downregulation of Tumor Suppressor gene PML in uterine cervical carcinogenesis: Impact of Human papillomavirus infection (HPV). N Singh, RC Sobti, V Suri, R Nijhawan, S Sharma, BC Das, M Bharadwaj, S Hussain. Gynecol Oncol 2013 Mar;128(3):420-426. 12 precancer, 118 cancer, 40 controls. "A significant downregulation of PML protein was observed in majority of cervical cancer and precancer cases 68% (89/130) compared to normal controls. The loss of expression pattern of PML gene was significantly increased with severity of disease both clinically and pathologically (p<0.001). HPV infection was detected in majority of cancer cases 96% (113/118) and in 83% (10/12) of pre cancer lesions whereas no infection could be detected in normal controls. Interestingly, all the 68% (89/130) cervical cancer cases that showed downregulation of PML were HPV infected (p=0.0001)."

Singh - Gynecol Oncol 2013 abstract / PubMed

HPV16 E7 Protein and hTERT Proteins Defective for Telomere Maintenance Cooperate to Immortalize Human Keratinocytes. J Miller, A Dakic, R Chen, N Palechor-Ceron, Y Dai, B Kallakury, R Schlegel, X Liu. PLoS Pathog 2013;9(4):e1003284. "Since hTERT has been shown to have a role in gene activation, we performed microarray studies and discovered that E6, hTERT and mutant hTERT proteins altered the expression of highly overlapping sets of cellular genes. Most important, the E6 and hTERT proteins induced mRNA and protein levels of Bmi1, the core subunit of the Polycomb Group (PcG) complex 1. We show further that Bmi1 substitutes for E6 or hTERT in cell immortalization. Finally, tissue array studies demonstrated that expression of Bmi1 increased with the severity of cervical dysplasia, suggesting a potential role in the progression of cervical cancer. Together, these data demonstrate that hTERT has extra-telomeric activities that facilitate cell immortalization and that its induction of Bmi1 is one potential mechanism for mediating this activity."

Miller / PLoS Pathog 2013 full article

Virological characteristics of cervical cancers carrying pure episomal form of HPV16 genome. JL Cheung, TH Cheung, MY Yu, PK Chan. Gynecol Oncol 2013 Nov;131(2):374-379. "Levels of the three E6/E7 mRNA transcripts in invasive cervical cancers containing purely episomal viral genome were found to be similar to those containing integrated viral genome, suggesting that cancers containing episomal viral genome were also mediated by an up-regulated E6/E7 mRNA expression, and more importantly, did not depend on integration and disruption of the E2 gene."

Cheung - Gynecol Oncol 2013 abstract / PubMed

Differences in the expression of human papillomavirus type 16 (HPV-16) E6 oncogene mRNA in SiHa cell line inoculated with CMV, HSV or ureaplasmas. S Szostek, B Zawilińska, M Biernat-Sudolska, J Kopeć, E Kłeszcz, M Koprynia, D Rojek-Zakrzewska, M Kosz-Vnenchak. Folia Biol (Krakow) 2014;62(1):73-78. "The presence of HSV-1 or HSV-2 in SiHa cells caused a 1.5-fold increase in HPV-16 E6 mRNA expression as compared with non-inoculated SiHa cells. Ureaplasma urealyticum presence but not Ureaplasma parvum stimulated the expression of HPV-16 E6 resulting in a nearly five-fold (4.8) up-regulated E6 mRNA level in SiHa cells."

Szostek - Folia Biol (Krakow) 2014 abstract / PubMed

Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Z Hu, D Zhu, W Wang, W Li, W Jia, X Zeng, W Ding, L Yu, X Wang, L Wang, H Shen, C Zhang, H Liu, X Liu, Y Zhao, X Fang, S Li, W Chen, T Tang, A Fu, Z Wang, G Chen, Q Gao, S Li, L Xi, C Wang, S Liao, X Ma, P Wu, K Li, S Wang, J Zhou, J Wang, X Xu, H Wang, D Ma. Nat Genet 2015 Feb;47(2):158-163. "[W]e identified 3,667 HPV integration breakpoints in 26 cervical intraepithelial neoplasias, 104 cervical carcinomas and five cell lines. Beyond recalculating frequencies for the previously reported frequent integration sites POU5F1B (9.7%), FHIT (8.7%), KLF12 (7.8%), KLF5 (6.8%), LRP1B (5.8%) and LEPREL1 (4.9%), we discovered new hot spots HMGA2 (7.8%), DLG2 (4.9%) and SEMA3D (4.9%). Protein expression from FHIT and LRP1B was downregulated when HPV integrated in their introns. Protein expression from MYC and HMGA2 was elevated when HPV integrated into flanking regions. Moreover, microhomologous sequence between the human and HPV genomes was significantly enriched near integration breakpoints, indicating that fusion between viral and human DNA may have occurred by microhomology-mediated DNA repair pathways."

Hu - Nat Genet 2015 abstract / PubMed

Transcriptionally Active Regions Are the Preferred Targets for Chromosomal HPV Integration in Cervical Carcinogenesis. IK Christiansen, GK Sandve, M Schmitz, M Dürst, E Hovig. PLoS One 2015 Mar 20;10(3):e0119566. "We find that integration sites coincide with DNA that is transcriptionally active in mucosal epithelium, as judged by the relationship of integration sites to DNase hypersensitivity and H3K4me3 methylation data. Finding an association between integration and transcription is highly informative with regard to the spatio-temporal characteristics of the integration process. These results suggest that integration is an early event in carcinogenesis, more than a late product of chromosomal instability."

Christiansen - PLoS One 2015 full article / PubMed Central
Christiansen / PLoS One 2015 full article

Stranglehold on the Spindle Assembly Checkpoint: The Human Papillomavirus E2 Protein Provokes BUBR1-dependent Aneuploidy. CL Tan, S Teissier, J Gunaratne, LS Quek, S Bellanger. Cell Cycle 2015;14(9):1459-1470. "The Human Papillomavirus (HPV) E2 protein, which inhibits the E6 and E7 viral oncogenes, is believed to have anti-oncogenic properties. Here, we challenge this view and show that HPV-18 E2 over-activates the Spindle Assembly Checkpoint (SAC) and induces DNA breaks in mitosis followed by aneuploidy. This phenotype is associated with interaction of E2 with the Mitotic Checkpoint Complex (MCC) proteins Cdc20, MAD2 and BUBR1. While BUBR1 silencing rescues the mitotic phenotype induced by E2, p53 silencing or presence of E6/E7 (inactivating p53 and increasing BUBR1 levels respectively) both amplify it. This work pinpoints E2 as a key protein in the initiation of HPV-induced cervical cancer and identifies the SAC as a target for oncogenic pathogens. Moreover, our results suggest a role of p53 in regulating the mitotic process itself and highlight SAC over-activation in a p53-negative context as a highly pathogenic event."

Tan - Cell Cycle 2015 abstract / PubMed

Epstein-Barr virus may be involved in early stages of cervical carcinogenesis

Epstein-Barr virus and p16INK4A methylation in squamous cell carcinoma and precancerous lesions of the cervix uteri. NR Kim, Z Lin, KR Kim, HY Cho, I Kim. J Korean Med Sci 2005 Aug;20(4):636-642. "p16-methylation and p16-immunoreactivities were higher in the EBV-positive group (p=0.009, p<0.001) than in the EBV-negative group... The p16 gene is one of the cell cycle regulating genes and encodes a nuclear protein, p16 which inhibits the D-type cyclin/cyclin-dependent kinase complexes that phosphorylate the retinoblastoma gene product (pRb), thus blocking G1-S cycle progression. The inactivation of p16 tumor suppressor gene promotes cell proliferation, and is found in many different types of carcinomas such as gastric carcinoma, bladder tumor, glioma, breast cancer and head and neck tumors. There is compelling evidence that the inactivation of p16 is an important genetic event in immortalization of keratinocytes. In previous studies of the p16 in cervical carcinomas, methylation specific polymerase chain reaction (PCR) has shown a high level of methylation, concordant with reports that the p16 gene is frequently inactivated through methylation rather than mutation or deletion... Non-neoplastic cervices showed unmethylation in all the cases, but 40% (12/30) of cervical intraepithelial neoplasms and 61% of invasive squamous cell carcinomas (25/41) showed p16 methylation (p=0.003, Fig. 1, Table 1)... Non-neoplastic cervices were immunonegative for p16 protein except for basal cells that are known to normally express p16 protein, but 53% of cervical intraepithelial neoplasm (16/30 cases) and 68.3% of invasive squamous cell carcinomas (28/41) expressed p16 protein. These results were significantly different among the four groups (p=0.001, Table 1, Fig. 2)... EBV was detected by EBNA-1 PCR in 9.1% of non-neoplastic cervical tissue (1/11), 36.7% of cervical intraepithelial neoplasm (11/30) and 36.6% of invasive squamous cell carcinomas (15/41) (Fig. 3)... Recent development of molecular genetics for carcinogenesis and virus, methylation of CpG islands possessing p16 is induced by the integration of viral DNA into host cells."

Kim - J Korean Med Sci 2005 full article / PubMed Central

Association between Epstein-Barr virus (EBV) and cervical carcinoma: A meta-analysis. MAP de Lima, PJN Neto, LPM Lima, J Gonçalves Júnior, AG Teixeira Junior, IPP Teodoro, HT Facundo, CGL da Silva, MVA Lima. Gynecol Oncol 2018 Feb;148(2):317-328. "[C]ervical carcinoma occurred four times as often among EBV positive women as in women without EBV infection (OR=4.01 [1.87-8.58]; p<0.001). The existence of EBV(+)HPV(-) carcinomas, the confirmed expression of latent oncoproteins (EBNA1, EBNA2, LMP1) and EBERs in tumor cells, and the association of EBV with the integration of high-risk-HPV DNA in malignant specimens point to EBV as a co-factor (so far underestimated) in the genesis and/or progression of cervical carcinoma."

de Lima - Gynecol Oncol 2018 abstract / PubMed

A Lie Made to Order for the Surgeon General

Smoking initiation is followed by the early acquisition of epigenetic change in cervical epithelium: a longitudinal study. YT Ma, SI Collins, LS Young, PG Murray, CB Woodman. Br J Cancer 2011 Apr 26;104(9):1500-1504. "To prove a causal link between an epigenetic change and an environmental or behavioural risk factor for a given disease, it is first necessary to show that the onset of exposure precedes the first detection of that epigenetic change in subjects who are still free of disease," they simper. In fact, according to the crooked definition causality which has been adoipted by the anti-smokers to facilitate the commission of scientific fraud, it is only necessary to show that exposure preceded disease, without any obligation to consider alternative explanations. Their subjects were recruited "soon after they first had sexual intercourse." (Why not recruit them BEFORE they have sex and possibly get HPV? This would help to avoid confounding -- ooops, that's exacly what these charlatans want to take advantage of!) They claim that "Among women who remained cytologically normal and who tested negative for human papillomavirus DNA in cervical smears during follow-up, those who first started to smoke during follow-up had an increased risk of acquiring CDKN2A [p16] methylation compared with never-smokers (odds ratio=3.67; 95% confidence interval 1.09-12.33; P=0.04). Conclusion: Smoking initiation is associated with the appearance of methylated forms of CDKN2A." But if this was true, there would be no point selecting subjects who are at risk for HPV in the first place! Plus, HPV is only PART of the story: Epstein-Barr virus also methylates p16!

Ma - Br J Cancer 2011 abstract - PubMed

The corrupt U.S. Surgeon General clique has embarked on a systematic campaign to falsely blame smoking for methylation of p16, by deliberately ignoring the role of infection. That means that garbage like this has been consciously perpetrated to commit scientific fraud.

Viruses and methylation of the p16 gene - The Surgeon General Lies About Cancer

Herpesviruses as possible cofactors in HPV-16-related oncogenesis. S Szostek, B Zawilinska, J Kopec, M Kosz-Vnenchak. Acta Biochim Pol 2009;56(2):337-342. "CMV DNA was more frequently present in samples with mixed forms of HPV-16 than in the episomal form (P < 0.025). Such a correlation was also observed in the case of EBV (P < 0.005). The presence of CMV resulted in a six-fold (OR 6.069; 95% CI 1.91-19.22; P = 0.002), while EBV caused a seven-fold (OR 7.11; 95% CI 1.70-29.67; P = 0.007) increase in the risk of the integrated or mixed HPV-16 genome occurrence."

Szostek / Acta Biochim Pol 2009 full article (pdf, 6 pp)

Association of EBV and HPV co-infection with the development of cervical cancer in ethnic Uyghur women. A Abudoukadeer, M Niyazi, A Aikula, M Kamilijian, X Sulaiman, A Mutailipu, A Abudula. Eur J Gynaecol Oncol 2015;36(5):546-550. 178 cases. "HPV-DNA was detectable in 2.5, 12.5, 68.0, and 96.4% of cases of cervicitis, CIN I, CIN II-III, and cervical cancer, respectively. For EBV-DNA, these numbers were 0, 3.1, 28.0, and 69.6%. There was a significant difference between the groups of cervicitis, CIN II-III, and cancer with respect to both HPV and EBV positivity rates (p < 0.05). Further analysis indicated that cervical lesion pathogenesis was not only accompanied by a gradually increasing rate of HPV or EBV-DNA alone, but also by an increasing rate of HPV-EBV dual infection (r = 0.46; p < 0.0 1). EBV protein expression was positive in 89.7% of EBV-DNA positive cases (34/39) and 6% of EBV-DNA negative cases (1/17)."

Abudoukadeer - Eur J Gynaecol Oncol 2015 abstract / PubMed

Possible contributing role of Epstein-Barr virus (EBV) as a cofactor in human papillomavirus (HPV)-associated cervical carcinogenesis. S Aromseree, C Pientong, P Swangphon, A Chaiwongkot, N Patarapadungkit, P Kleebkaow, T Tungsiriwattana, B Kongyingyoes, T Vendrig, JM Middeldorp, T Ekalaksananan. J Clin Virol 2015 Oct 23;73:70-76. 82 cervical tissues with no squamous intraepithelial lesions, 85 low-grade SILs, 85 high-grade SILs, and 40 squamous cell carcinomas. "EBV was detected increasingly from noSIL (13.4%), LSIL (29.4%) to HSIL (49.4%) samples. The prevalence of HPV-EBV co-infection was significantly higher in any grade of lesion than in noSIL samples (p<0.05) including noSIL (1.2%; 95% confidence intervals [CI]=0.0-3.6%, relative risk [RR]=1), LSIL (18.8%, 95% CI=10.5-27.1%, RR=15.4), HSIL (41.2%, 95% CI=30.7-51.6%, RR=33.8) and SCC (30.0%, 95% CI=15.8-44.2%, RR=24.6). Interestingly, HPV-EBV co-infection was more common in cases with episomal forms of high-risk (HR) HPV whereas HPV alone was more common in cases with integrated HR-HPV. In addition, EBER staining demonstrated that EBV was mainly present in infiltrating lymphocytes." [However, EBER is less expressed in well differentiated squamous cell carcinomas of the nasopharynx - cast]

Aromseree - J Clin Virol 2015 abstract / PubMed


Human papillomavirus type 16 E6 and E7 cooperate to increase epidermal growth factor receptor (EGFR) mRNA levels, overcoming mechanisms by which excessive EGFR signaling shortens the life span of normal human keratinocytes. GS Akerman, WH Tolleson, KL Brown, LL Zyzak, E Mourateva, TS Engin, A Basaraba, AL Coker, KE Creek, L Pirisi. Cancer Res 2001 May 1;61(9):3837-3843. "[A]lthough HKc strains expressing relatively low basal EGFR levels grew poorly and tolerated the infection protocol with difficulty, they responded to E6 with an increase in EGFR mRNA and protein and with robust proliferation. However, those HKc strains expressing high basal EGFR levels grew well, but did not respond to E6 with increased EGFR levels or with proliferation. Immunostaining of paraffin-embedded foreskin tissue for the EGFR confirmed that there is an intrinsic interindividual variability of EGFR expression in HKC... We conclude that both E6 and E7 contribute to increasing EGFR levels, but with different mechanisms: although E6 can increase EGFR levels, it cannot overcome the resistance of normal HKc to excessive EGFR signaling. On the other hand E7, which alone does not acutely increase EGFR mRNA or protein, allows for EGFR overexpression in normal HKC."

Akerman / Cancer Res 2001 full article

Requirement of epidermal growth factor receptor for hyperplasia induced by E5, a high-risk human papillomavirus oncogene. SM Genther Williams, GL Disbrow, R Schlegel, D Lee, DW Threadgill, PF Lambert. Cancer Res 2005 Aug 1;65(15):6534-6542. "Cervical cancer is a progressive disease that takes on average one to two decades to develop. During that period, the HPV genome is maintained as a nuclear plasmid in the infected cervical epithelium, and early genes, including E5, are expressed. Thus, E5 has the potential to contribute to the HPV-associated carcinogenic process. In cervical cancer itself, however, HPV genomes commonly are found integrated into the host cellular genome, and this occurs such that the E6 and E7 ORFs remain intact, but E5 is lost or, if present, underexpressed compared with E6 and E7 (39–41). This suggests that E5 may play a critical role in the genesis of cervical cancer but less of a role in its persistence or progression... Our K14E5 mice provide an opportunity to assess directly the role of E5 in cervical carcinogenesis. In the original HPV transgenic mouse model for cervical cancer, estrogen was found to synergize with the early region of HPV16 present in K14HPV16 mice, including the E5, E6, and E7 oncogenes, to induce cervical cancer that bore histopathologic features very similar to that seen in human cervical cancer (42). More recently, the individual roles of E6 and E7 oncogenes have been elucidated using our previously generated K14E6 and K14E7 mice that express the HPV16 E6 and E7 oncogenes individually (43). It is interesting to note that the estrogen-treated K14E6/K14E7 doubly transgenic mice had lower mean numbers of cancers per mouse than seen with the K14HPV16 mice expressing all three oncogenes (43). This difference in tumor number could be due to a difference in the expression level of the two transgenes or due to the participation of another early viral protein, such as E5, in the genesis of cervical cancer. What is striking about our initial studies reported here is that the early age of onset and high penetrance of spontaneous skin tumors arising in our K4E5 mice indicates that HPV16 E5 is far more potent an oncogene than we have observed for either HPV16 E6 or E7 in our existing K14E6 and K14E7 mouse models."

Genther Williams / Cancer Res 2005 full article

See also "HPV Strains and Oncogenicity"
See also "EBV & Socioeconomic Status"

HPV and mannose-binding lectin - MBL mediates phagocytosis and activates complement, and is a component of the innate immune defense against numerous infections


Association between MBL2 gene functional polymorphisms and high-risk human papillomavirus infection in Brazilian women. V Guimaraes, R Guimaraes, L Brandao, MF Baldez da Silva, M Milanese, L Segat, H Castelletti, D Bruneska, JL de Lima Filho, AC de Freitas, LC Arraes, C Rocha, S Crovella. Hum Immunol 2008 Apr-May;69(4-5):273-278. 180 high-risk HPV-infected women (99 with cancer and 81 without) and 180 healthy controls. "When considering combined genotypes grouped according to MBL production (designated as high, low, and deficient producers), we detected a significant difference between healthy controls and high-risk HPV-positive patients, the latter group showing increased frequencies of deficient-producer genotypes (14.4% vs 9.4% in the healthy control group, corrected p = 0.04)."

Guimaraes - Hum Immunol 2008 abstract / PubMed

Mannose-binding lectin in high-risk human papillomavirus infection. CC Tsai, TM Lin, HL You, HL Eng. Am J Obstet Gynecol 2009 Jun;200(6):618.e1-6. 150 patients with HPV and 277 control subjects with no HPV. "Mannose-binding lectin (MBL) is a serum lectin that mediates phagocytosis and activates complement... The frequency of high-producer mbl-2 genotypes was higher in patients with HPV than in control subjects with no HPV (P = .001)."

Tsai CC - Am J Obstet Gynecol 2009 abstract / PubMed

MBL2 gene polymorphisms are correlated with high-risk human papillomavirus infection but not with human papillomavirus-related cervical cancer. L Segat, S Crovella, M Comar, M Milanese, N Zanotta, A Fabris, C Trevisiol, T Rossi, F De Seta, C Campello. Hum Immunol 2009 Jun;70(6):436-439. 172 women with high-risk HPV, "105 of whom had HPV-related squamous cell carcinoma of the cervix (SCC), as well as 105 women not infected by HPV. We demonstrated an association of MBL2 polymorphisms with high-risk HPV infection in women without SCC who showed increased presence of the mutant MBL2 0 allele and 0/0 genotype as compared with women with SCC and healthy controls."

Segat - Hum Immunol 2009 abstract / PubMed


The Effect of Aging of Formalin-fixed Paraffin-embedded Tissues on the In Situ Hybridization and Immunohistochemistry Signals in Cervical Lesions. AJ Nuovo, M Garofalo, A Mikhail, AF Nicol, C Vianna-Andrade, GJ Nuovo. Diagn Mol Pathol 2013 Sep;22(3):164-173. "There was a progressive and statistically significant decrease in the strength of the p16 signal when comparing tissues prepared from recent unstained slides (0 to 1 y old, mean score of 92%) to those of intermediate age (5 to 7 y old, mean score of 49%) to old unstained slides (cut 13 to 15 y ago, mean score of 10%). Equivalent, progressive, and significant decreases in the intensity of the signals for microRNAs, CD45, and human papillomavirus DNA were seen in tissues stored on slides from 5 to 7 years and 13 to 15 years, respectively. However, the diminution of signal was much less, although still statistically significant, if the sections from the 13- to 15-year-old paraffin blocks were prepared in 2012."

Nuovo - Diagn Mol Pathol 2013 abstract / PubMed

Impact of age on the false negative rate of human papillomavirus DNA test in patients with atypical squamous cells of undetermined significance. KH Won, JY Lee, HY Cho, DH Suh, JH No, YB Kim. Obstet Gynecol Sci 2015 Mar;58(2):117-123. 439 patients. "In patients with ASCUS, the false negative rate of HPV test for CIN2+ was 6.2%. The false negative rate of the HPV test became higher with increasing of the age after the age of 50 (P=0.034)."

Won - Obstet Gynecol Sci 2015 full article / PubMed Central
Won / Obstet Gynecol Sci 2015 full article

Lies About Smoking and Cervical Cancer

The Lie That Smoking Interacts With HPV Infection

This latest and "greatest" piece of disinformation purports that "Women who smoke and also carry high levels of the virus associated with cervical cancer are up to 27 times more likely to develop the most common form of cervical cancer compared with uninfected women who also smoke." In point of fact, virtually ALL cervical cancer patients (~99.7%) are actually infected with HPV, and it is likewise for its precursor lesions. Worst of all, they considered only HPV-16, when there are several other types which are known to cause cervical cancer. We can be certain that all of the cases were infected by HPV, and these sleasy "investigators" (propagandists) simply failed to detect the other types. In the actual study, they attempt to weasel: "Another limitation of our study relates to a lack of information on infection with other HPV types than HPV-16 in the smears. This potentially prevents us from adjusting completely for HPV in the analyses of smoking as a main effect." This is a lie, it absolutely prevents them from doing so, not just "potentially." "However, we do adjust for number of sexual partners, which could be regarded as a good proxy for acquiring an HPV infection." This is a lie, because this proxy variable has been proven to be inadequate to prevent confounding. Another deception: "'Clearly, both exposures need to be present at the same time for there to be interaction,' Gunnell said." Well, duh, that is self-evident. But merely noting that both are present does not demonstrate an interaction. The clear intent is to create the false impression that this study found one, when it did not. In addition, the newspaper article lies that smoking and HPVs "are both known to contribute to the disease on their own," when this is true only for HPV. (Smoking increases risk of cervical cancer. By Lee Bowman. Scripps Howard News Service, Nov. 18, 2006. Re: Synergy between Cigarette Smoking and Human Papillomavirus Type 16 in Cervical Cancer In situ Development. AS Gunnell, TN Tran, A Torrang, PW Dickman, P Sparen, J Palmgren, N Ylitalo. Cancer Epidemiol Biomarkers Prev 2006 Nov;15(11):2141-2147.)

Smoking increases risk of cervical cancer, Nov. 18, 2006 / Seattle Post Intelligencer
Gunnell / Cancer Epidemiol Biomarkers Prev 2006 full article (pdf, 7pp)

A clumsy anti-smoker fraud

The Cigarette Smoke Carcinogen Benzo[a]pyrene Enhances Human Papillomavirus Synthesis. S Alam, MJ Conway, H-S Chen, Craig Meyers. Journal of Virology 2008 Jan;82(2):1053-1058. This one has all the hallmarks of a fraud deliberately concocted for the use of the anti-smokers: "Epidemiological studies suggest that cigarette smoke carcinogens are cofactors which synergize with human papillomavirus (HPV) to increase the risk of cervical cancer progression. Benzo[a]pyrene (BaP), a major carcinogen in cigarette smoke, is detected in the cervical mucus and may interact with HPV. Exposure of cervical cells to high concentrations of BaP resulted in a 10-fold increase in HPV type 31 (HPV31) viral titers, whereas treatment with low concentrations of BaP resulted in an increased number of HPV genome copies but not an increase in virion morphogenesis. BaP exposure also increased HPV16 and HPV18 viral titers. Overall, BaP modulation of the HPV life cycle could potentially enhance viral persistence, host tissue carcinogenesis, and permissiveness for cancer progression."

Alam - J Virol 2008 abstract / PubMed

One thing wrong with their story is that increased viral titers indicate a productive infection, which are the kind that kill the cells, thus removing the chance that they will become cancers. Another is their hysteria about Benzo[a]pyrene (BaP), a supposed major carcinogen in cigarette smoke. Smoking is actually a minor source of it compared to dietary sources. "[T]he food chain is the dominant pathway of human exposure, accounting for about 97% of the total daily intake of BaP. Inhalation and consumption of contaminated water are only minor pathways of human exposure [2% from air, and 1% from water]. The long-term average daily intake of BaP by the general population is estimated to be 2.2 micrograms (ug) per day. Cigarette smoking and indoor activities do not substantially increase human exposure to BaP relative to background levels of BaP present in the environment." And, "[A]verage smokers (i.e., individuals who smoke 20 cigarettes a day) are taking in an additional 780 ng of BaP daily, which means that smokers get an additional 16% BaP from smoking" [based on pre-1979 cigarettes, which contained about twice the quantity of BaP as newer low-tar cigarettes]. Also, the exposure from cooked beef (0.2 -24.1 ug/kg) is less than the exposure from leafy vegetables (7.0 - 48 ug/kg). (Benzo-a-pyrene: Environmental partitioning and human exposure. H.A. Hattemer-Frey, C.C. Travis. Toxicology and Industrial Health 1991;7(3):141-157.) Nobody smokes through their vagina, so they cannot pretend that local levels of BaP there are higher due to direct exposure to smoke. Anybody who was really concerned about the effect of BaP, as opposed to merely manufacturing deceitful propaganda, would would have taken actual human exposure to it into account.

Hattemer-Frey & Travis, Toxicology and Industrial Health 1991 / UCSF (pdf, 17 pp)

Exposed: The lie that smoking supposedly suppresses immunity by reducing the number of cervical Langerhans cells

Tobacco smoking impairs the local immunosurveillance in the uterine cervix. An immunohistochemical study. WA Poppe, PS Ide, MP Drijkoningen, JM Lauweryns, FA Van Assche. Gynecol Obstet Invest 1995;39(1):34-38. The subjects were 38 premenopausal patients undergoing hysterectomy for noncervical benign pathology, with normal PAP smears, which does not exclude the possibility of HPV infection.

Poppe - Gynecol Obstet Invest 1995 abstract / PubMed
Poppe - Gynecol Obstet Invest 1995 full article / UCSF (pdf, 5 pp)

Toll-Like Receptors 7, 8, and 9 Expression and Function in Primary Human Cervical Cancer Langerhans Cells: Evidence of Anergy. MM Kumar, S Adurthi, S Ramachandran, G Mukherjee, O Joy, H Krishnamurthy, S Krishna, UD Bafna, DK Uma, RS Jayshree. Int J Gynecol Cancer 2013 Jan;23(1):184-192. "Cervical tumor LCs lacked TLR9 expression and were functionally anergic to all the 3: TLR7, TLR8, and TLR9 ligands, which may play a crucial role in immune tolerance." HPV 16 was "one of the common human papillomavirus types in all cases."

Kumar - Int J Gynecol Cancer 2013 abstract / PubMed

The E6, E7 and L2 proteins of human papillomavirus reduce the number of Langerhans cells

Depletion of Langerhans cells in human papillomavirus type-16 infected skin is associated with E6-mediated down regulation of E-cadherin. K Matthews, CM Leong, L Baxter, E Inglis, K Yun, BT Backstrom, J Doorbar, M Hibma. J Virology 2003 Aug;77(15):8378-8385. "Adhesion between keratinocytes (KC) and LC [Langerhans cells], mediated by E-cadherin, is important in the retention of LC in the skin. Cell surface E-cadherin is reduced on HPV16-infected basal KC, and this is directly asociated with the reduction in numbers of LC in infected epidermis. Expression of a single viral early protein, HPV16 E6, in KC reduces levels of cell surface E-cadherin thereby interfering with E-cadherin-mediated adhesion." This reduces the presentation of antigen by the Langerhans cells, and helps prevent the initiation of a cell-mediated immune response.

Matthews / J Virology 2003 full article

Decreased migration of Langerhans Precursor-Like Cells in response to human keratinocytes expressing human papillomavirus Type 16 E6/E7 is related to reduced Macrophage Inflammatory Protein-3{alpha} Production. JC Guess, DJ McCance J Virol. 2005 Dec;79(23):14852-14862. "[F]ollowing proinflammatory stimulus, HPV-16 E6 and E7 inhibit MIP-3alpha transcription, resulting in suppression of the migration of immature Langerhans precursor-like cells. Interestingly, the E6 and E7 proteins from the low-risk HPV types also inhibited MIP-3-alpha transcription. These results suggest that one mechanism by which HPV-infected cells suppress the immune response may be through the inhibition of a vital alert signal, thus contributing to the persistence of HPV infection."

Guess / J Virol 2005 full article

High-risk human papilloma virus infection decreases the frequency of dendritic Langerhans' cells in the human female genital tract. R Jimenez-Flores, R Mendez-Cruz, J Ojeda-Ortiz, R Muñoz-Molina, O Balderas-Carrillo, M de la Luz Diaz-Soberanes, S Lebecque, S Saeland, A Daneri-Navarro, A Garcia-Carranca, SE Ullrich, L Flores-Romo. Immunology 2006 Feb;117(2):220-228. 16 positive and five negative women. "DC frequency per area was substantially reduced (to approximately 50% for the three markers) in samples from all HPV-infected patients compared with samples from controls. Unlike HPV(-) samples, Langerin(+) DC in HPV(+) cervix exhibited a highly accentuated dendritic appearance."

Jimenez-Flores - Immunology 2006 full article / PubMed Central

A major role for the minor capsid protein of human papillomavirus type 16 in immune escape. LM Fahey, AB Raff, DM Da Silva, WM Kast. J Immunol 2009 Nov 15;183(10):6151-6156. "We demonstrate that LC exposed to the minor capsid protein L2 in HPV16L1L2 virus-like particles do not phenotypically or functionally mature. However, HPV16L1 virus-like particles significantly induce activation of LC. Our data suggest that the L2 protein plays a specific role in the induction of this immune escape of HPV16 through the manipulation of LC."

Fahey / J Immunol 2009 full article

Epigenetic repression of E-cadherin by human papillomavirus 16 E7 protein. J Laurson, S Khan, R Chung, K Cross, K Raj. Carcinogenesis 2010 May;31(5):918-926. "A common feature shared between several human cancer-associated viruses, such as Epstein-Barr virus, Hepatitis B virus and Hepatitis C virus, and Human papillomavirus (HPV) is the ability to reduce the expression of cellular E-cadherin. Since E-cadherin is used by Langerhans cells to move through the stratified epithelium, its reduction may affect the efficiency by which the immune system responds to HPV infection and the length of persistent HPV infections. We observed that the E7 protein of this virus (HPV16) is most efficient at reducing E-cadherin levels. This E7 activity is independent of retinoblastoma protein or AP-2alpha degradation. Instead it is associated with augmentation of cellular DNA methyltransferase I (Dnmt1) activity. Significantly, inhibition of Dnmt activity re-established E-cadherin levels of the cells, presenting the possibility that similar epigenetic intervention clinically may be a way to re-establish the influx of Langerhans cells into infected epithelium to counteract HPV persistence."

Laurson - Carcinogenesis 2010 full article / PubMed Central

Deregulation of E-cadherin by human papillomavirus is not confined to high-risk, cancer-causing types. CM Leong, J Doorbar, I Nindl, HS Yoon, MH Hibma. Br J Dermatol 2010 Dec;163(6):1253-1263. 47 lesions infected by α, β, γ and μ HPVs. "Surface E-cadherin was reduced in tissues infected with members of the α4, α7 and α9 species and the γ and μ genera but was equivalent to normal epidermis in the β only-infected lesions tested and patchy in α10-infected tissues. There was a direct relationship between atypical E-cadherin expression and a significant reduction in LCs. Expression of P-cadherin, a protein that is increased in the E-cadherin constitutive knockout mouse, was increased in lesions with reduced E-cadherin... E-cadherin expression was reduced or lost in epidermis irrespective of the cancer risk of the infecting HPV type or the ability of the virus to degrade retinoblastoma protein or p53."

Leong - Br J Dermatol 2010 abstract / PubMed

Transcriptional repression of e-cadherin by human papillomavirus type 16 e6. ZJ D'Costa, C Jolly, EJ Androphy, A Mercer, CM Matthews, MH Hibma. PLoS One 2012;7(11):e48954. "We found that the E-cadherin promoter is repressed in cells expressing E6, resulting in fewer E-cadherin transcripts. On exploring the mechanism for this, repression by increased histone deacetylase activity or by increased binding of trans-repressors to the E-cadherin promoter Epal element was discounted. In contrast, DNA methyltransferase (DNMT) activity was increased in E6 expressing cells. Upon inhibiting DNMT activity using 5-Aza-2'-deoxycytidine, E-cadherin transcription was restored in the presence of HPV16 E6. The E-cadherin promoter was not directly methylated, however a mutational analysis showed general promoter repression and reduced binding of the transactivators Sp1 and AML1 and the repressor Slug. Expression of E7 with E6 resulted in a further reduction in surface E-cadherin levels."

D'Costa - PLoS One 2012 full article / PubMed CentralD'Costa / PLoS One 2012 full article

Inhibition of langerhans cell maturation by human papillomavirus type 16: a novel role for the annexin A2 heterotetramer in immune suppression. AW Woodham, AB Raff, LM Raff, DM Da Silva, L Yan, JG Skeate, MK Wong, YG Lin, WM Kast. J Immunol 2014 May 15;192(10):4748-4757. "An N-terminal peptide of HPV16 L2 (aa 108-126) has been shown to specifically interact with A2t. In this study, we show that incubation of human LC with this peptide blocks binding of HPV16. Inhibiting this interaction with an A2t ligand or by small interfering RNA downregulation of A2t significantly decreases HPV16 internalization into LC in an L2-dependent manner. A2t is associated with suppression of LC maturation as demonstrated through attenuated secretion of Th1-associated cytokines and decreased surface expression of MHC class II on LC exposed to A2t."

Woodham - J Immunol 2014 abstract / PubMed

Exposed: The lie that smoking causes mutations of the Fragile Histidine Triad gene

The National Cancer Institute (e.g., Popescu and DiPaulo) have known for over a decade that HPV causes these mutations.

Regional chromosome localization of human papillomavirus integration sites near fragile sites, oncogenes, and cancer chromosome breakpoints. LA Cannizzaro, M Durst, MJ Mendez, BK Hecht, F Hecht. Cancer Genet Cytogenet 1988 Jul 1;33(1):93-98. "For the cell line, the viral integration site was mapped to chromosome region 8q21-q22.3, while in the primary tumor chromosome band 3p21 was the target for integration. The HPV DNA integration appears to occur in the vicinity of fragile sites, oncogenes, and chromosome breakpoints that are characteristic of hematologic malignancies and solid tumors."

Cannizzaro - Cancer Genet Cytogenet 1988 abstract / PubMed

Integration of human papillomavirus 16 DNA and genomic rearrangements in immortalized human keratinocyte lines. NC Popescu, JA DiPaolo. Cancer Res 1990 Feb 15;50(4):1316-1323. "... Thus, for the first time in an experimental system, HPV16 integration into the cellular genome was associated with the induction of a subset of chromosome alterations. HPV16 integration that frequently occurred at fragile sites and near protooncogenes may be a critical alteration which confers a selective growth advantage and an indefinite proliferative potential to HPV-transfected cells." "In situ localization of HPV DNA in these cell lines implicates the integration of viral DNA to the formation of persistent structural changes. Significantly, HPV sequences of cervical carcinoma cell lines integrated on normal and abnormal chromosomes near fragile sites and protooncogene locations."

Popescu - Cancer Res 1990 abstract / PubMed
Popescu / Cancer Res 1990 full article

FRA3B extends over a broad region and contains a spontaneous HPV16 integration site: Direct evidence for the coincidence of viral integration sites and fragile sites. CM Wilke, BK Hall, A Hoge, W Paradee, DI Smith, TW Glover. Hum Mol Genet 1996;5:187–195. "We further show that an area of frequent gaps and breaks within FRA3B, defined by a lambda contig, coincides with a previously characterized site of HPV16 integration in a primary cervical carcinoma. The HPV16 integration event gave rise to a short chromosomal deletion limited to the local FRA3B region within 3p14.2. Interestingly, 3p14.2 lies within the smallest commonly deleted region of 3p in cervical cancers, which are often HPV16 associated."

Wilke / Hum Mol Genet 1996 full article

Common fragile sites are preferential targets for HPV16 integrations in cervical tumors. EC Thorland, SL Myers, BS Gostout, DI Smith. Oncogene 2003 Feb 27;22(8):1225-1237. "Our data demonstrate that 11/23 HPV16 integrations in cervical tumors occurred within CFSs (P&<0.001). In addition, we show that deletions and complex rearrangements frequently occur in the cellular sequences targeted by the integrations and that integrations cluster in FRA13C (13q22), FRA3B (3p14.2), and FRA17B (17q23). Finally, our data suggest that cellular genes, such as Notch 1, are disrupted by the HPV16 integrations, which may contribute to the malignant phenotype."

Thorland - Oncogene 2003 abstract / PubMed

Systematic review of genomic integration sites of human papillomavirus genomes in epithelial dysplasia and invasive cancer of the female lower genital tract. N Wentzensen, S Vinokurova, MvK Doeberitz. Cancer Res 2004 Jun 1;64(11):3878-3884. "Up to now, in total, 192 individual HPV integration sites have been described in primary tumor samples and cell lines. Here, we summarize all available data on chromosomal HPV integration sites. The data suggest that integration of HR-HPV genomes occurs relatively late in the progression of high-grade cervical dysplasia. It appears that integration of HR-HPV genomes is a consequence of an overall destabilization process of the chromosomal integrity in replicating epithelial stem cells that express the viral E6-E7 oncogenes. The consequences of the structural alterations of the viral genome and the impact of cellular sequences on its transcriptional regulation seem to be more important than functional alteration of specific cellular genes by the integrated viral sequences."

Wentzensen / Cancer Res 2004 full article

Characterization of naturally occurring HPV16 integration sites isolated from cervical keratinocytes under noncompetitive conditions. KL Dall, CG Scarpini, I Roberts, DM Winder, MA Stanley, B Muralidhar, MT Herdman, MR Pett, N Coleman. Cancer Res 2008 Oct 15;68(20):8249-8259. "Of 24 different integration sites isolated from a single nonclonal population of W12, 12 (50%) occurred within chromosome bands containing a common fragile site (CFS), similar to observations for selected integrants in vivo. This suggests that such regions represent relatively accessible sites for insertion of foreign DNA, rather than conferring a selective advantage when disrupted."

Dall / Cancer Res 2008 full article

Identification of human papillomavirus type 16 integration sites in high-grade precancerous cervical lesions. M Matovina, I Sabol, G Grubisić, NM Gasperov, M Grce. Gynecol Oncol 2009 Apr;113(1):120-127. "Sequencing of 11 DIPS amplicons revealed HPV DNA from 6 samples (54.5%) to be integrated in cellular genes (VMP1, PVRL1, CHERP, CEACAM5, AHR, MRF-2) and also 6 (54.5%) within the common fragile sites (CFS)."

Matovina - Gynecol Oncol 2009 abstract / PubMed

The liars ignore the fact that smokers are more likely to be exposed to HPV, and at younger ages, which they have exploited to falsely blame smoking for cervical cancer from the very beginning.

The fragile histidine triad gene: a molecular link between cigarette smoking and cervical cancer. CH Holschneider, RL Baldwin, K Tumber, C Aoyama, BY Karlan. Clin Cancer Res 2005 Aug 15;11(16):5756-5763. Their claim is merely that the integration was more common among smokers, which is easily attributable to the cancers being of a later stage of development, but not of a different pattern.

Holschneider / Clin Cancer Res 2005 full article

The American Cancer Society

The American Cancer Society still lies that smoking causes cervical cancer. (Smoking May Double Cervical Cancer Risk. American Cancer Society, 2004/01/19.) They use a defective study that ignores the infections in the women's sexual partners, which is contrary to accepted practice in regard to other sexually transmitted diseases, and enables them to exploit higher rates of HPV infection in the sexual partners of women smokers. (Smoking and cervical cancer: pooled analysis of the IARC multi-centric case-control study. M Plummer, R Herrero, S Franceschi, CJLM Meijer, P Snijders, FX Bosch, S de Sanjose, N Munoz. Cancer Causes and Control 2003 Nov;14(9):805-814.) Note that Bosch, de Sanjose, and Munoz were authors of the letter to Phillips and Smith in the International Journal of Epidemiology 1994, in which they admitted that the results of their past studies had been confounded by undetected HPV infection, and that when HPV infection was taken into account, there was no increased risk of cervical cancer in smokers. These people do not need to be told that sexual partners are a key factor in sexual transmitted diseases, it is axiomatic. And this study demonstrates that, instead of recognizing the potential for confounding and avoiding it, they exploited as a new mechanism for manufacturing anti-smoking hate propaganda.

Smoking May Double Cervical Cancer Risk / American Cancer Society
Plummer / Cancer Causes and Control 2003 abstract

"Only a small percentage of women with certain types of abnormal cells resulting from HPV infection will develop cancer if these cells are not removed and destroyed. Studies suggest that whether a person will develop cancer depends on a variety of factors that act together with HPVs. These factors include smoking, decreased resistance to infection, and infection with other viruses, such as human immunodeficiency virus (HIV)." (Human Papillomavirus (HPV). ACS, revised 03-06-2000.)

The ACS lies again that "Smoking is another risk factor for cervical cancer. Tobacco smoke can produce chemicals that may damage the DNA in cells of the cervix and make cancer more likely to develop. Women who smoke are about twice as likely as non-smokers to get cervical cancer." From: "Cervical Cancer - Overview." ACS, revised 03-16-2000.

"Smoking exposes the body to many cancer-causing chemicals that affect more than the lungs. These harmful substances are absorbed by the lungs and carried in the bloodstream throughout the body. Tobacco by-products have been found in the cervical mucus of women who smoke. Researchers believe that these substances damage the DNA of cells in the cervix and may contribute to the development of cervical cancer. Women who smoke are about twice as likely as nonsmokers to get cervical cancer." They also lie that "Not smoking is another way to reduce the risk of cervical cancer and precancer." (Pap Test. American Cancer Society, 12-03; What Are the Risk Factors for Cervical Cancer, 8-04.) This is the stereotypical deceitful format of health fascist "scary chemicals" propaganda. FACT: Even active smokers are exposed to only 16% more of the combustion product benzo(a)pyrene than nonsmokers; 97% of exposure to it comes from ordinary food, including vegetables. FACT: With modern analytical equipment, trace amounts of anything can be found practically anywhere. FACT: The "researchers" who blame smoking are corrupt hacks whom the Cancer Society nurtures in order to further their health fascist political agenda. And, even after decades of trying, they still haven't identified any mechanism of carcinogenesis. FACT: The lie that smokers are twice as likely to get cervical cancer is based on deliberately falsely blaming smoking for cervical cancer that is actually caused by HPV infection.

Pap Test / American Cancer Society
What Are the Risk Factors for Cervical Cancer / American Cancer Society

As usual, the ACS uses defective studies that failed to detect all HPV and failed to measure the amount of exposure to it, in order to falsely blame smoking. And, here is the truth regarding the dubious role of chemical carcinogens: "Attempts to determine the importance of cofactors utilizing in vitro models with human cells and recombinant HPV have been frustrating. In general, there is a marked contrast between the effects of a carcinogen on rodent and human cells. Whereas a number of chemical and physical viral agents are effective in transforming normal rodent cells to the malignant state, they are for the most part ineffective when applied to human cells. The same can be said for cells that have been immortalized with HPV-16 or -18. The addition of diverse chemical carcinogens to HPV-16 immortalized cells has consistently failed to induce malignancy; however, evidence of effects has been obtained as reflected by new chromosomal arrangements." (Immortalization of human keratinocytes by human papillomaviruses. CD Woodworth, JA DiPaolo. In: DNA tumor viruses. Oncogenic mechanisms. G Barbanti-Brodano, M Bendinelli, H Friedman, eds. Plenum Press, 1995, Ch 6, pp 91-109.)

Co-author DiPaolo is an old mouse painter from the 1950s, and is cited in the 1964 Surgeon General report (Effect on mice of oral painting of cigarette smoke condensates. DiPaolo JA, Moore GE. J Nat Cancer Inst 1959;23:529-534). For more than 40 years, enormous resources have been devoted to fruitless efforts to find some mechanism of chemical carcinogenesis by which to blame smoking. It is certainly not for lack of trying that they have failed. Lacking such a discovery, they resort to pretending that the long-sought discovery is imminent (Introduction of sister chromatid exchanges by tobacco-specific nitrosamine 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in human and hamster cells. D Zimonjic, NC Popescu, JA DiPaolo. Carcinogenesis 1989 Apr;10(4):753-755. The poor man must indeed have had a frustrating life, but not nearly as frustrating as those who have been the targets of this propaganda.

Woodworth & DiPaolo / NCI Laboratory of Biology

The National Cancer Institute

The National Cancer Institute continues to officially lie about smoking and cervical cancer. From their previous lie that "Cigarette smoking may be associated with an increased risk of cervical cancer. Many studies have shown an association while other studies have not," they have now escalated their lie: "Cigarette smoking is associated with an increased risk of cervical cancer." (Cervical Cancer (PDQ) Prevention - Patients. National Cancer Institute, 7/13/2005.)

Cervical Cancer Prevention (for patients) / (PDQ), NCI

The NCI lies even more floridly to health professionals. Their old lie: "Cigarette smoking by women is associated with an increased risk for squamous cell carcinoma. This risk increases with longer duration and intensity of smoking and may be present with exposure to environmental tobacco smoke as well, being as high as 3 times that of women who are nonsmokers and are not exposed to environmental tobacco smoking. Some studies demonstrate an increased risk for current smoking only as opposed to former smokers, suggesting that carcinogens in cigarette smoke exert a late stage effect on carcinogenesis." Their new lie: "Based on solid evidence, cigarette smoking, both active and passive, increases the risk of cervical cancer." "Magnitude of Effects on Health Outcomes: Among HPV-infected women, current and former smokers have approximately 2 to 3 times the incidence of high-grade cervical intraepithelial neoplasia or invasive cancer. Passive smoking is also associated with increased risk, but to a lesser extent." (Cervical Cancer (PDQ) Prevention, Health Professional Version. National Cancer Institute, 7/20/2005.)

Cervical Cancer Prevention (for health professionals) / (PDQ), NCI

Meanwhile, on their General Information page, NCI admits that "Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, which far outweighs other known risk factors such as high parity, increasing number of sexual partners, young age at first intercourse, low socioeconomic status, and positive smoking history." What they don't admit is that studies which ignore HPV falsely blame non-causal "risk factors," including smoking and passive smoking. And, even in studies which do consider it, there may be residual confounding due to false negatives, and to different amounts of exposure to the virus from infected versus uninfected male partners. (General Information. Cervical Cancer (PDQ®): Treatment. Last Modified: 05/18/2006.)

Cervical Cancer (PDQ®): Treatment /

The Cancer Research Campaign

The Cancer Research Campaign in the UK also lies. Their old lie: "Smoking also increases the risk of cancer of the cervix, although it is not clear exactly how or why. The risk increases with the number of cigarettes a woman smokes each day and with the number of years she has smoked." Their updated lie: "Research shows that smoking increases the risk of developing cervical cancer, possibly because smoking weakens the immune system's ability to eliminate HPV." (Cervical Cancer. Cancer Research Campaign, 20/12/2004.)

Cervical Cancer / Cancer Research Campaign

Health Canada

"In some studies, cigarette smoking has been found to increase the risk." This is weaseling. The studies that find these alleged risks are the ones with residual confounding by HPV infection (or which ignore it entirely). (Screening for cervical cancer. Health Canada, 2005-08-09.)

Screening for Cervical Cancer / Health Canada

The Johns Hopkins University

This claim from Dr. Anthony J. Alberg of Johns Hopkins University is deliberate, willful, reckless, knowing, SCIENTIFIC FRAUD, because the confounding effect of failure to fully detect exposure to human papillomavirus is thoroughly documented, and there is no excuse for ignoring it. This study is nothing but a lifestyle questionnaire, deliberately exploiting the different rates of exposure of smokers and passive smokers versus non-smokers, in order to fraudulently claim, for hate propaganda purposes, that secondhand smoke causes cervical cancer. Their study design is inherently defective for its pretended purpose; its results are entirely due to different rates of exposure to HPV; and their facile line that smoking depresses immunity is nothing but a smokescreen. (Active and passive cigarette smoking and the risk of cervical neoplasia. CL Trimble, JM Genkinger, AE Burke, SC Hoffman, KJ Helzlsouer, M Diener-West, GW Comstock, AJ Alberg. Obstetrics and Gynecology 2005 Feb 1;105:174-181.)

Trimble / Obstetrics & Gynecology 2005

And then they spew their poisonous lies for mass consumption: Passive Smoking Linked to Cervical Cancer. By Anthony J. Brown, MD. ReutersHealth, Jan. 21, 2005; Cervical Cancer Tied to Secondhand Smoke. By Katrina Woznicki. WomensENews Jan. 25, 2005.

Passive Smoking Linked to Cervical Cancer /
Woznicki Jan. 25, 2005 / Women's E News

See also:

Confounding By Infection
HPV Strains and Oncogenicity
HPV Causes Head and Neck Cancers
HPV Causes Oral Cancer
HPV is implicated in laryngeal cancer
HPV Causes Lung Cancer HPV DNA has been detected in 24.5% of 4508 lung cancers [2009] and the same high risk types implicated in other squamous cell cancers have been identified.
HPVs Cause Skin Cancer
HPV Infects Kids HPV infection including oncogenic types is common in children

National Cervical Cancer Coalition - has also picked up on the HPV link to lung cancer


cast 01-12-20