Adenoviruses Are Implicated in Lung Cancer

EXAMPLE: "Despite its spectacular achievements, the first successful form of gene therapy will for now be used only as a last resort due to the risk of cancer. And that's not the only bad news. The latest studies suggest that some other gene therapies using different viruses might also trigger cancer. The Necker hospital in Paris pioneered the use of gene therapy to cure the severe inherited immune disease called X-SCID. But two of the 11 boys treated have developed leukemia. Both these cases appear to be due to the corrective gene being inserted near another gene called Lmo2, which helps control cell growth and can contribute to cancer if turned on at the wrong time (New Scientist, 25 January, p 12). Calculations by Christof von Kalle of the University of Cincinnati College of Medicine in Ohio suggest that rather than being an extraordinary coincidence the engineered mouse retrovirus used to deliver the gene in the French study may insert it near Lmo2 about once per 100,000 insertions. Since millions of bone marrow cells are modified and returned to the boys, such insertions may crop up in most if not all of the patients." (Cancer risk clouds gene cures. New Scientist March 15, 2003. Gene therapy 'caused T-cell leukemia.' By Jo Lyford. The Scientist Oct. 20, 2003; a third child later developed leukemia: January 2005, third adverse event in Paris! By Sandro Rusconi. Swiss Gene Therapy Web Page.) Although adenovirus was not used in this therapy, the principle is the same. And, what they do not mention in these articles is that the same thing may happen in natural infections - but, despite foreboding evidence, there has been little or no investigation before the establishment rushed into gene therapy.

Cancer risk clouds gene therapy / Eurekalert
Gene therapy 'caused T-cell leukemia' / The Scientist
January 2005, third adverse event in Paris! / Swiss Gene Therapy Web Page

PROBLEM WITH A POTENTIAL ENGINEERED ADENOVIRUS THERAPY, OBSERVED IN LABORATORY: E1B55K-deleted adenovirus (ONYX-015) overrides G1/S and G2/M checkpoints and causes mitotic catastrophe and endoreduplication in p53-proficient normal cells. G Cherubini, T Petouchoff, M Grossi, S Piersanti, E Cundari, I Saggio. Cell Cycle 2006 Oct;5(19):2244-2252. " In order to take advantage of cell replication machinery, viruses have evolved complex strategies to override cell cycle checkpoints and force host cells into S phase. To do so, virus products must interfere not only with the basal cell cycle regulators, such as pRb or Mad2, but also with the main surveillance pathways such as those controlled by p53 and ATM. Recently, a number of defective viruses has been produced which, lacking the latter ability, are incapable of replicating in normal cells but should be able to grow and finally lyse those cells that, such as the tumor cells, have lost their surveillance mechanisms. A prototype of these oncolytic viruses is the E1B55K-defective Adenovirus ONYX-015, which was predicted to selectively replicate and kill p53-deficient cancer cells. We found that, despite wt p53 and notwithstanding the activation of the checkpoint regulators p53, ATM and Mad2, ONYX-015 actively replicated in HUVEC cells. Furthermore, ONYX-015 replication induced a specific phenotype, which is distinct from that of the E4-deleted adenovirus dlE4 Ad5, although both viruses express the main regulatory region E1A. This phenotype includes overriding of the G(1)/S and G(2)/M checkpoints, over-expression of MAD2 and retardation of mitosis and accumulation of polyploid cells, suggesting the occurrence of alterations at the mitotic-spindle checkpoint and impairment of the post-mitotic checkpoint. Our data suggest that viral E1A and E4 region products can override all host cell-checkpoint response even at the presence of a full activation of the ATM/p53 pathway. Furthermore, the E4 region alone seems to act independently of the E1B55K virus product in impairing the ATM-dependent, p53-independent G(2)/M checkpoint since dlE4 Ad5-infected cells arrested in G(2) while ONYX-015-infected cells did enter mitosis."

Cherubini - Cell Cycle 2006 abstract / PubMed

An online review of adenoviruses, which however expresses the "conventional wisdom" about the nononcogenicity of adenoviruses in humans: "In 1962, some adenoviruses were shown to cause tumors in rodents -- this caused a considerable panic (N.B. Adenovirus oncogenesis appears to be associated with abortive infections and has never been observed in humans.)" Mainly because there was never a serious effort to look.

Adenoviruses / Tulane

The role of the Tobacco Industry Research Council and the National Institutes of Health in adenovirus cancer research in the 1960s:

To Viruses and Cancer, 1962: What They Knew

In the 1960s and early 1970s, the National Cancer Institute funded some seroepidemiological studies of adenoviruses versus various types of cancer. They established nothing more than that exposure to adenoviruses was very common. Some were conducted by Maurice Green, RJ Huebner's leading contractor in the NCI's Cancer Virus Program, at St. Louis University, Huebner's alma mater, where Green was a professor. On the basis of these, Green and RV Gilden, of Huebner's Flow Laboratory, concluded that "Adenoviruses are not thought likely to be an important cause of human cancer" (Adenoviruses in human cancer. RM McAllister, RV Gilden, M Green. The Lancet 1972 Apr 15;1(7755):831-833; no abstract available). In the latter 1970s, a pitifully small sample of cancers were investigated for the presence of adenoviral DNA (the same four small cell lung cancers were used in the three 1979 studies), and the reported negative results were considered sufficient to dismiss the idea that adenoviruses could cause human cancer. Research that was directly relevant to human disease dried up, and the resurgence of research since 1994 is mainly concerned with the use of adenoviruses as vectors in gene therapy. And, in the meantime, the anti-smoking racketeers conspired to make it a thought crime to suggest that there could be any alternative cause for lung cancer other than smoking.

The "Special Virus Cancer Program" Masquerade

In 1969, Dr. Frank J. Rauscher, an associate scientific director of the National Cancer Institute and head of its cancer virus program, claimed that adenoviruses had been all but removed from suspicion of causing cancer, and killed off 380 monkeys in the NCI's research program who had just reached an age when cancer would be expected to develop.

Rauscher's Monkey Massacre

Do highly oncogenic group A human adenoviruses cause human cancer? Analysis of human tumors for adenovirus 12 transforming DNA sequences. JK Mackey, PM Rigden, M Green. Proc Natl Acad Sci 1976 Dec;73(12):4657-4661. These included 17 squamous and 5 adenocarcinomas, but no small cell lung cancers.

Mackey - PNAS 1976 Full Article / PubMed Central

Analysis of human cancer DNA for DNA sequences of human adenovirus type 4. JK Mackey, M Green, WSM Wold, P Rigden. J Natl Cancer Inst 1979 Jan;62(1):23-26.

Mackey - JNCI 1979 abstract / PubMed

Analysis of human cancer DNA's for DNA sequences of human adenovirus serotypes 3, 7, 11, 14, 16 and 21 in Group B. WSM Wold, JK Mackey, P Rigden, M Green. Cancer Res 1979 Sep;39(9):3479-3484.

Wold - Cancer Res 1979 abstract / PubMed

Analysis of human tonsil and cancer DNAs and RNAs for DNA sequences of group C (serotypes 1, 2, 5, and 6) human adenoviruses. M Green, WSM Wold, JK Mackey, P Rigden. Proc Natl Acad Sci 1979 Dec;76(12):6606-6610.

Green - PNAS 1979 Full Article / PubMed Central

Investigation resumes

Detection of group C adenovirus DNA in small-cell lung cancer with the nested polymerase chain reaction. K Kuwano, M Kawasaki, R Kunitake, N Hagimoto, Y Nomoto, T Matsuba, T Nakanishi, N Hara. J Cancer Res Clin Oncol 1997;123(7):377-382. "E1A target DNA was present in 11 (31%) of 35 cases of small-cell lung cancer but in none of the 40 cases of non-small-cell lung cancer (P<0.01). Of the 11 cases found positive by PCR, 8 were positive for adenovirus DNA by in situ hybridization."

Kuwano - J Cancer Res Clin Oncol 1997 abstract / PubMed

The American Cancer Society says of small cell lung cancer: "About 20% of all lung cancers are of this type... Small cell lung cancer is almost always caused by smoking. It is very rare for someone who has never smoked to have small cell lung cancer. Other names for small cell lung cancer are oat cell carcinoma and small cell undifferentiated carcinoma" ( In ACS News Today 1999 Sep 17, they call it "the type of lung cancer most strongly linked with exposure to tobacco... Small cell lung cancer accounts for about 25 percent of all lung cancers" (


To the American Cancer Society and the National Cancer Institute, adenoviruses have historically been of interest only as gene therapy vectors. They are concerned enough about the possibility of inadvertently causing cancers in patients to remove the suspect genes from these viral vectors - at least the ones they know about. BUT THEY ARE STONEWALLING ABOUT CANCER CAUSED BY ALL THOSE NATURAL INFECTIONS WITH WILD-TYPE VIRUSES THAT HAVE ALL THEIR GENES. Just look at the nature of the research on adenoviruses. There's a flood of adenovirus vector research, versus virtually nothing on the role of natural adenoviruses in any cancer. The void speaks for itself.

Adenovirus AND cancer / PubMed

Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity. DM Shayakhmetov, A Gaggar, S Ni, Z-Y Li, A Lieber. J Virology 2005 Jun;79(12):7478-7491. Adenovirus vectors cause inflammation of the liver.

Shayakhmetov / J Virol 2005 abstract


Adenovirus proteins inhibit cell death and transform cells

Oncogenic potential of the adenovirus E4orf6 protein. M Moore, N Horikoshi, T Shenk. PNAS 1996 Oct;93(10):11295-11301. They note that "Although several early studies described the presence of E4-specific mRNAs in addition to the E1A and E1B species in adenovirus transformed rat and hamster cells (e.g., refs. 39-41; reviewed in ref. 42), a role for E4 in transformation was discounted because it was not always present in cells transformed by adenovirus types 2 and 5 and because cloned E1A and E1B genes were sufficient for transformation." The studies cited date from 1975, and about that time there was "The Big Push to Suppress Virus Work," and investigate only chemical carcinogens. Incidentally, "This work [the present paper] was supported by grants from the National Cancer Institute (CA41086) and the Cystic Fibrosis Foundation. T.S. is an American Cancer Society Professor and an Investigator of the Howard Hughes Medical Institute."

Moore / PNAS 1996 full article
To The Big Push to Suppress Virus Work

The cell death inhibitor Bcl-2 and its homologues influence control of cell cycle entry. LA O'Reilly, DC Huang, A Strasser. EMBO J 1996 Dec 16;15(24):6979-6790.

O'Reilly - EMBO J 1996 abstract / PubMed

Bcl-2, Bcl-XL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. DC Huang, S Cory, A Strasser. Oncogene 1997 Jan 30;14(4):405-414.

Huang - Oncogene 1997 abstract / PubMed

The adenovirus E4orf6 protein can promote E1A/E1B-induced focus formation by interfering with p53 tumor suppressor function. M Nevels, S Rubenwolf, T Spruss, H Wolf, T Dobner. PNAS 1997 Feb;94(2):1206-1211. "There is accumulating evidence that other viral proteins from different DNA tumor viruses -- i.e., human papillomavirus E6, hepatitis B virus Hbx, and Epstein-Barr virus BZLF-1 -- bind to the carboxyl region of p53. Given the importance of this domain in the regulation of the tumor-suppressor function of p53, these protein interactions may represent a general mechanism by which these viruses modulate p53 function and trigger oncogenic transformation."

Nevels / PNAS 1997 full article

Adenovirus E1B 55K represses p53 activation in vitro. MED Martin, AJ Berk. J Virol 1998 Apr;72(4):3146-3154. "The cellular phosphoprotein p53 acts as a tumor suppressor, and inactivation of this function is the most prevalent alteration found in human and animal tumors..."

Martin / J Virol 1998 full article

Transforming potential of the adenovirus type 5 E4orf3 protein. M Nevels, B Tauber, E Kremmer, T Spruss, H Wolf, T Dobner. J Virol 1999 Feb;73(2):1591-1600. They observed that like E4orf6, E4orf3 disappeared from cell lines after transformation. "The absence of the viral DNA templates in these transformants implies that both E4 gene products can transform primary cells with E1A by a 'hit and run' mechanism." [Nevels is co-author with 1988-98 CTR member PK Vogt of a chapter on "Cell transformation by viruses," in a 1996 book co-edited by 1982-86 CTR member Peter Howley, which is cited in the lead paragraph of the present paper. Howley was forced to resign from the CTR. Needless to say, none of this has ever been brought up in a tobacco trial - cast]

Nevels / J Virol 1999 full article
To The CTR Was a Lasker Loot-A-Thon (Peter M. Howley)

The adenovirus E4orf6 protein contributes to malignant transformation by antagonizing E1A-induced accumulation of the tumor suppressor protein p53. M Nevels, T Spruss, H Wolf, T Dobner. Oncogene 1999 Jan 7;18(1):9-17.

Nevels - Oncogene 1999 abstract / PubMed

Adenovirus E4 34k and E4 11k inhibit double strand break repair and are physically associated with the cellular DNA-dependent protein kinase. J Boyer, K Rohleder, G Ketner. Virology 1999 Oct 25;263(2):307-312. "The adenovirus oncoproteins E4 34k and E4 11k, the products of E4 open reading frames 6 and 3, respectively, individually prevent the formation of concatemers of the linear viral genome in infected cells."

Boyer - Virology 1999 abstract / PubMed

Two distinct activities contribute to the oncogenic potential of the adenovirus type 5 E4orf6 protein. M Nevels, S Rubenwolf, T Spruss, H Wolf, T Dobner. J Virol 2000 Jun;74(11):5168-5181.

Nevels / J Virol 2000 full article

Identification of three functions of the adenovirus E4orf6 protein that mediate p53 degradation by the E4orf6-E1B55K complex. E Querido, MR Morrison, Huan Chu-Pham-Dang, SW-L Thirlwell, D Boivin, PE Branton. J Virol 2001 Jan;75(2):699-709.

Querido / J Virol 2001 full article

Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex. Genes Dev 2001 Dec 1;15(23):3104-3117.

Querido - Genes Dev 2001 abstract / PubMed
Querido - Genes Dev 2001 Full Article

Regulation of the mitochondrial checkpoint in p53-mediated apoptosis confers resistance to cell death. H Henry, A Thomas, Y Shen, E White. Oncogene 2002 Jan 24;21(5):748-760.

Henry - Oncogene 2002 abstract / PubMed

Adenovirus and cell cycle control. H Ben-Israel, T Kleinberger. Front Biosci 2002 May 1;7:d1369-95. E1A proteins inactivate the pRb checkpoint, and E1B and E4orf6 inactivate p53.

Ben-Israel - Front Biosci 2002 abstract / PubMed

Nuclear export of adenovirus E4orf6 protein is necessary for its ability to antagonize apoptotic activity of BH3-only proteins. M Aoyagi, F Higashino, M Yasuda, A Takahashi, Y Sawada, Y Totsuka, T Kohgo, H Sano, M Kobayashi, M Shindoh. Oncogene 2003 Oct 9;22(44):6919-6927. "Here, we demonstrate that the adenovirus E4orf6 protein inhibits apoptosis mediated by BNIP3 and Bik, which are BH3-only proteins of the Bcl-2 family. This activity was not mediated by p53 and p73 because E4orf6 had the same effect on the apoptosis in Saos-2 cells that do not express p53-related genes. It was also ascertained that E4orf6 could change the mitochondrial localization of BNIP3 and Bik. A mutant lacking the nuclear export signal of E4orf6 failed to inhibit apoptosis and to translocate BNIP3 protein from the mitochondria. Moreover, it was also established that E4orf6 was able to interact with BNIP3 and Bik. In BNIP3 protein, the region required for the interaction included the transmembrane domain, which is required for the localization of BNIP3 to the mitochondria. These results suggest that E4orf6 is exported from the nucleus to the cytoplasm, enabling it to interact with BH3-only proteins, eventually leading to the inhibition of apoptotic activity."

Aoyagi - Oncogene 2003 abstract / PubMed

Identification of the E1A-regulated transcription factor p120 E4F as an interacting partner of the RASSF1A candidate tumor suppressor gene. SL Fenton, A Dallol, A Agathanggelou, L Hesson, J Ahmed-Choudhury, S Baksh, C Sardet, R Dammann, JD Minna, J Downward, ER Maher, F Latif. Cancer Res 2004 Jan 1;64(1):102-107. "We identified the E1A-regulated transcription factor p120(E4F) as a RASSF1A interacting partner in yeast and mammalian cells, and demonstrated that RASSF1A protein and p120(E4F) form a complex in vivo. The interaction between RASSF1A and p120(E4F) was confirmed by both in vitro and in vivo pull downs and coimmunoprecipitation assays."

Fenton - Cancer Res 2004 abstract / PubMed

E1A-based determinants of oncogenicity in human adenovirus groups A and C. JF Williams, Y Zhang, MA Williams, S Hou, D Kushner, RP Ricciardi. Curr Top Microbiol Immunol 2004;273:245-288. Review. "A broad spectrum of genetic and molecular investigations carried out with group C, Ad2 and Ad5, and with group A, Ad12, have shown that early region1 (E1) gene products are sufficient for complete transformation of rodent cells in vitro by these viruses... In this chapter we review previous findings and present new evidence which demonstrates that Ad12 E1A possesses two or more independent functions enabling it to induce tumors. One of these functions lies in its capacity to repress transcription of MHC class I genes, allowing the tumor cells to avoid lysis by cytotoxic T lymphocytes... In addition to mediating immune escape, E1A also determines the susceptibility of transformants to Natural Killer (NK) cell lysis, and in this case, also, Ad12 transformants are not susceptible."

Williams - Curr Top Microbiol Immunol 2004 abstract / PubMed

The adenovirus E4orf6 protein inhibits DNA double strand break repair and radiosensitizes human tumor cells in an E1B-55K-independent manner. LS Hart, SM Yannone, C Naczki, JS Orlando, SB Waters, SA Akman, DJ Chen, D Ornelles, C Koumenis. J Biol Chem 2005 Jan 14;280(2):1474-1481.

Hart - J Biol Chem 2005 abstract / PubMed

Adenovirus type 5 early region 1B 156R protein promotes cell transformation independent from repression of p53-stimulated transcription. T Sieber, T Dobner. J Virol 2007 Jan;81(1):95-105. Two gene products of Early region 1B (E1B) of adenovirus type 5 (Ad5), E1B-19K and E1B-55K, are individually capable of cooperating with the Ad5 E1A proteins to completely transform rodent cells in culture. The remaining E1B proteins are E1B-156R, E1B-93R and E1B-84R. E1B-156R also enhances focal transformation of primary rat cells in cooperation with E1A. "Since E1B-156R seemed unable to relocalise p53 and inhibit its transactivating function, it must be assumed that it contributes to transformation independently of repression of p53-stimulated transcription. Furthermore, we discovered that E1B-156R contains a functional transcriptional repression domain and binds Ad5 E4orf6 and the cellular apoptosis regulator Daxx. While the ability to bind E4orf6 could indicate further biological functions of E1B-156R in viral infection, the interaction with Daxx might also be linked to its transforming potential. Taken together, these analyses introduce E1B-156R as a novel transformation-promoting E1B protein that acts without repressing p53-transactivation. Moreover, identification of the interaction partners E4orf6 and Daxx provide a first glance of E1B-156R's potential functions."

Sieber / J Virol 2007 full article
Sieber - J Virol 2007 full article / PubMed Central

Viral oncoproteins target the DNA methyltransferases. WA Burgers, L Blanchon, S Pradhan, Y de Launoit, T Kouzarides, F Fuks. Oncogene 2007 Mar 8;26(11):1650-1655. "Here, we show that adenovirus 5 E1A and HPV-16 E7 associate in vitro and in vivo with the DNA methyltransferase Dnmt1. Consistent with this interaction, we find that E1A and E7 can purify DNA methyltransferase activity from nuclear extracts. These associations are direct and mediated by the extreme N-terminus of E1A and the CR3 zinc-finger domain of E7. Furthermore, we find that a point mutant at leucine 20 of E1A, a residue known to be critical for its transformation functions, is unable to bind Dnmt1 and DNA methyltransferase activity."

Burgers - Oncogene 2007 abstract / PubMed

Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes. HB Fleisig, NI Orazio, H Liang, AF Tyler, HP Adams, MD Weitzman, L Nagarajan. Oncogene 2007 Jul 19;26(33):4797-4805. "Sequence-specific single-stranded DNA-binding protein 2 (SSBP2) is a candidate tumor suppressor for human acute myelogenous leukemia (AML). Inducible expression of SSBP2 causes growth arrest and partial differentiation in AML cells. Here, we report that the adenoviral oncoprotein E1B55K directly binds to endogenous SSBP2 protein and sequesters it into juxtanuclear bodies in adenovirally transformed human embryonic kidney (HEK) 293 cells... These data demonstrate that E1B55K targets the candidate leukemia suppressor SSBP2 and suggest that subverting its function may contribute to cell transformation by viral oncoproteins."

Fleisig - Oncogene 2007 abstract / PubMed

In Vivo Potential Effects of Adenovirus Type 5 E1A and E1B on Lung Carcinogenesis and lymphoproliferative Inflammation. Y Yang, C McKerlie, Z Lu, L Wang, M Buchwald. J Virol 2008 Aug;82(16):8105-8111. In transgenic mice, "Preferential expression of Ad5 E1A 243 aa protein alone was not sufficient to induce lung carcinogenesis, but resulted in low-grade cellular proliferation and high-grade lymphoproliferative inflammation in the lung. The presence of Ad5 E1B dramatically enhanced the expression of E1A 243 aa protein, in addition to impaired p53 and apoptosis response, resulting in uncontrolled cellular proliferation, lymphoproliferative inflammation and metastatic carcinomas in the lung after a period of latency."

Yang / J Virol 2008 full article

Induction of Neuronal and Tumor-related Genes by Adenovirus Type 12 E1A. H Guan, JF Williams, RP Ricciardi. J Virol 2009 Jan;83(2):651-661. "Adenovirus type 12 (Ad12) E1A protein (E1A-12) contains a unique 20-amino-acid spacer region between the second and third conserved regions. Substitution of a single amino acid in the spacer is able to abrogate Ad12 tumorigenesis. To investigate the function of the spacer, microarray analysis was performed on cells transformed by tumorigenic and nontumorigenic Ad12s that differ only by one amino acid in the spacer. Fewer than 0.8% of approximately 8,000 genes in the microarray exhibited differential expression of threefold and higher. Of these, more than half of the known genes with higher expression in the wild-type Ad12-transformed cells have neuronal-specific functions. Some of the other differentially expressed genes are involved in the regulation of the cell cycle, transcription, cell structure, and tumor invasiveness. Northern blot analyses of a subset of the neuronal genes, including Robo1, N-MYC, and -internexin, confirmed their strong expression in multiple Ad12 tumorigenic cell lines. In contrast, these neuronal genes displayed only minor or negligible expression in cells transformed by spacer-mutated Ad12. Significantly, stable introduction of E1A-12 into nontumorigenic Ad5-transformed cells induced neuronal gene expression."

Guan / J Virol 2009 abstract

Serotype-specific inactivation of the cellular DNA damage response during adenovirus infection. NA Forrester, GG Sedgwick, A Thomas, AN Blackford, T Speiseder, T Dobner, PJ Byrd, GS Stewart, AS Turnell, RJ Grand. J Virol 2011 Mar;85(5):2201-2211. Adenovirus type 5 inactivates the host cell DNA damage response by facilitating the degradation of Mre11, DNA ligase IV and p53. In the case of p53 this is achieved through polyubiquitylation by Ad5E1B55K and Ad5E4orf6 which recruit a Cul5-based E3 ubiquitin ligase. Recent evidence indicates that this paradigm does not apply to other adenovirus serotypes, since Ad12, but not Ad5, causes degradation of TOPBP1 through the action of E4orf6 alone and a Cul2-based E3 ubiquitin ligase. We have now extended these studies to adenovirus groups A-E. Whilst infection by Ad4, 5 and 12 (groups E, C and A, respectively) cause degradation of Mre11, DNA ligase IV and p53, infection with Ad3, 7, 9 and 11 (groups B1, B1, D and B2 respectively) only affects DNA ligase IV levels. Indeed, Ad3, 7 and 11 cause the marked accumulation of p53. Despite this, MDM2 levels were very low following infection with all the viruses examined here, regardless of whether they increase p53 expression. In addition, we found that only Ad12 causes degradation of TOPBP1, and, like Ad5, Ad4 recruits a Cul5-based E3 ubiquitin ligase to degrade p53. Surprisingly, Mre11 and DNA ligase IV degradation do not appear to be significantly affected in Ad4, 5 or 12 infected cells depleted of Cul2 or Cul5, indicating that E1B55K and E4orf6 recruit multiple ubiquitin ligases to target cellular proteins. Finally, although Mre11 is not degraded by Ad3, 7, 9 and 11 no viral DNA concatemers could be detected. We suggest that group B and D adenoviruses have evolved mechanisms based on loss of DNA ligase IV and perhaps other unknown molecules to disable the host cell DNA damage response to promote viral replication."

Forrester - J Virol 2011 abstract / PubMed

The Human Adenovirus E4-ORF1 Protein Subverts Discs Large 1 to Mediate Membrane Recruitment and Dysregulation of Phosphatidylinositol 3-Kinase. K Kong, M Kumar, M Taruishi, RT Javier. PLoS Pathog 2014 May 1;10(5):e1004102. In Ad9, "The adenovirus E4-ORF1 gene encodes an oncoprotein that promotes viral replication, cell survival, and transformation by activating phosphatidylinositol 3-kinase (PI3K). While the mechanism of activation is not understood, this function depends on a complex formed between E4-ORF1 and the membrane-associated cellular PDZ protein... These results demonstrate that E4-ORF1 interacts with Dlg1 and PI3K to assemble a ternary complex where E4-ORF1 hijacks the Dlg1 oncogenic function to relocate cytoplasmic PI3K to the membrane for constitutive activation. This novel mechanism of Dlg1 subversion by adenovirus to dysregulate PI3K could be used by other pathogenic viruses, such as human papillomavirus, human T-cell leukemia virus type 1, and influenza A virus, which also target Dlg1 and activate PI3K in cells." Also: "Results of soft agar and focus formation assays implicated the ternary complex and its activation of PI3K in E4-ORF1-induced transformation of a human epithelial line that retains features of normal epithelial cells (Figure 14). This finding reinforces concerns that the use of adenovirus vectors retaining the E4-ORF1 gene for vaccination or various therapies, as well as the proposed use of the Ad36 E4-ORF1 gene to treat fatty liver disease and liver dysfunction or to improve glycemic control, may increase patient risk for developing neoplasms."

Kong / PLoS Pathog 2014 full article

Hijacking Discs Large 1 for Oncogenic Phosphatidylinositol 3-Kinase Activation in Human Epithelial Cells Is a Conserved Mechanism of Human Adenovirus E4-ORF1 Proteins. M Kumar, K Kong, RT Javier. J Virol 2014 Dec;88(24):14268-14277. "Results showed that in human MCF10A epithelial cells, stable expression of E4-ORF1 proteins encoded by representative human adenovirus serotypes from subgroups A to D induce ternary complex formation, Dlg1-dependent PI3K activation, PI3K protein elevation, Dlg1 and PI3K membrane recruitment, and PI3K-dependent cellular transformation. The first three of these E4-ORF1 activities were also observed in MCF10A cells infected with each wild-type human adenovirus from subgroups A to D. Our findings indicate that most, if not all, human adenovirus E4-ORF1 proteins share a conserved molecular mechanism of PI3K activation, which confers a common capacity to promote oncogenic transformation in human epithelial cells... The results raise potential safety concerns about the use of vectors encoding the E4-ORF1 gene in human gene therapy and vaccination."

Kumar - J Virol 2014 full article / PubMed Central
Kumar / J Virol 2014 full article

Adenovirus E4-ORF1 Dysregulates Epidermal Growth Factor and Insulin/Insulin-Like Growth Factor Receptors To Mediate Constitutive Myc Expression. K Kong, M Kumar, M Taruishi, RT Javier. J Virol 2015 Nov 1;89(21):10774-10785. "In this study, we showed that E4-ORF1 hijacks the tyrosine kinase activities of cellular epidermal growth factor receptor (EGFR) and insulin receptor (InsR)/insulin-like growth factor receptor 1 (IGF1R), as well as the lipid kinase activity of PI3K, to mediate constitutive Myc protein expression. We additionally demonstrated that EGFR contributes to constitutive Myc expression through the capacity of E4-ORF1 to induce ligand-independent EGFR activation and stimulation of the Ras/Mek/Erk pathway, the latter activity of which was conserved by human adenoviruses. Results further suggested that EGFR normally forms a complex with the cellular PDZ protein Discs Large 1 (Dlg1), a component of the Dlg1:E4-ORF1:PI3K ternary complex that mediates E4-ORF1-induced PI3K activation, and that E4-ORF1 binds the Dlg1:EGFR complex and promotes the association of EGFR with InsR and IGF1R. In addition to its role in constitutive Myc expression, InsR/IGF1R also negatively regulates EGFR autophosphorylation and EGFR-mediated Ras/Mek/Erk signaling, and data suggested that E4-ORF1 binding to Dlg1 antagonizes these activities. Collectively, our findings suggest that in human epithelial cells, E4-ORF1 targets EGFR, InsR/IGF1R, and PI3K at the plasma membrane to activate cytosolic signaling pathways that sustain Myc protein levels in the nucleus. We postulate that E4-ORF1-induced constitutive Myc expression functions to ensure the formation of nuclear E4-ORF1:Myc complexes, which have been shown to activate Myc and to enhance adenovirus replication."

Kong - J Virol 2015 abstract / PubMed

Adenovirus Integration

Cloning and sequencing of the cellular-viral junctions from the human adenovirus type 5 transformed 293 cell line. N Louis, C Evelegh, FL Graham. Virology 1997 Jul 7;233(2):423-429. "The Ad5 sequences... are located in the pregnancy-specific beta-1-glycoprotein 4 (PSG 4) gene. This maps the insertion of Ad5 DNA to human chromosome 19 (19q13.2)."

Louis - Virology 1997 abstract / PubMed

From the Online Mendelian Inheritance in Man (OMIM): "The human pregnancy-specific glycoproteins (PSGs) are a group of molecules that are mainly produced by the placental syncytiotrophoblasts during pregnancy..." They are believed to be essential for normal pregnancy. High levels are found in patients with choriocarcinoma and hydatidiform mole.


Chromosome damage

Chromosomal damage induced by human adenovirus type 12 requires expression of the E1B 55-kilodalton viral protein. S Schramayr, D Caporossi, I Mak, T Jelinek, S Bacchetti. J Virol 1990 May;64(5):2090-2095. "Infection of human embryonic kidney cells with adenovirus type 12 results in the induction of damage at specific (17q21-22, 1p36, 1q21, and 1q42-43) and random sites in the cellular chromosomes... Our results show that the expression of the E1A proteins is not sufficient for this effect. On the other hand, mutations within the E1B 55-kilodalton protein but not the E1B 19-kilodalton protein affect the ability of the virus to induce both specific and random chromosomal damage."

Schramayr - J Virol 1990 Full Article / PubMed Central

Adenovirus type 12-induced fragility of the human RNU2 locus requires p53 function. Z Li, A Yu, AM Weiner. J Virol 1998 May;72(5):4183-4191. "We propose a model for Ad12-induced chromosome fragility in which interaction of p53 with the Ad12 E1B 55-kDa transforming protein (and possibly E4orf6) induces a p53 gain of function which ultimately perturbs the RNA polymerase II basal transcription apparatus. The p53 gain of function could interfere with chromatin condensation either by blocking mitotic shutdown of U1 and U2 snRNA transcription or by phenocopying global or local DNA damage."

Li - J Virol 1998 Full Article

Coexpression of the adenovirus 12 E1B 55 kDa oncoprotein and cellular tumor suppressor p53 is sufficient to induce metaphase fragility of the human RNU2 locus. D Liao, A Yu, AM Weiner. Virology 1999 Feb 1;254(1):11-23. "Although Ad12 E1B 55 kDa efficiently induced fragility in transfected cells, Ad2 E1B 55 kDa did not. By swapping domains between the Ad12 and Ad2 E1B, we found that the aminoterminus of Ad12 E1B is required for induction of fragility and that the ability of the hybrid E1B proteins to induce fragility appears to correlate with nuclear localization. Furthermore, in Saos-2 cells lacking p53 function, RNU2 fragility could be induced by cotransfection with vectors encoding Ad12 E1B 55 kDa and either wild-type p53 or the R273H mutant with impaired DNA binding activity."

Liao - Virology 1999 abstract / PubMed

RNA, U1 Small Nuclear; RNU1, located at 1p36.3


RNA, U2 Small Nuclear; RNU2, located at 17q21-q22. (OMIM).


Ribonucleic Acid, Ribosomal, 5S; 5S rRNA; RN5S; located at 1q42.11-q42.13.


"Hit-and-run" transformation

"According to classical concepts of viral oncogenesis, the persistence of virus-specific oncogenes is required to maintain the transformed cellular phenotype. In contrast, the "hit-and-run" hypothesis claims that viruses can mediate cellular transformation through an initial "hit," while maintenance of the transformed state is compatible with the loss ("run") of viral molecules." Cells that are transformed by adenovirus E1A and E1B permanently express these viral genes. However, a new mechanism of transformation has been found in which oncoproteins E4orf6 or E4orf3 cooperate with E1A in place of E1B. These cells do not express the E4 gene products, and only a subset contain E1A proteins. They conclude, "Our results strongly support the possibility that even tumors that lack any detectable virus-specific molecules can be of viral origin, which could have a significant impact on the use of adenoviral vectors for gene therapy." The health establishment is heavily invested in adenovirus-vector gene therapy; will they try to cover this up for this reason as well? "Hit-and-run" transformation by adenovirus oncogenes. M Nevels, B Tauber, T Spruss, H Wolf, T Dobner. J Virol 2001 Apr;75(7):3089-3094.

Nevels / J Virol 2001 full article

(AN EXAMPLE OF E4ORF6 IN GENE THERAPY RESEARCH): Improved adeno-associated virus vector production with transfection of a single helper adenovirus gene, E4orf6. JM Allen, CL Halbert, AD Miller. Mol Ther 2000 Jan;1(1):88-95.

Allen - Mol Ther 2000 abstract / PubMed

Adenovirus interactions with other viruses

Human cytomegalovirus IE1 and IE2 proteins are mutagenic and mediate "hit-and-run" oncogenic transformation in cooperation with the adenovirus E1A proteins. Y Shen, H Zhu, T Shenk. Proc Natl Acad Sci USA 1997 Apr;94(7):3341-3345.

Shen / PNAS 1997 full article
Shen / PNAS - PubMed Central full article

Human papilloma virus E6 and E7 proteins support DNA replication of adenoviruses deleted for the E1A and E1B genes. DS Steinwaerder, CA Carlson, A Lieber. Mol Ther 2001 Sep;4(3):211-216. The implications of co-infection in vivo with both HPV and Ad are not addressed.

Steinwaerder - Mol Ther 2001 abstract / PubMed

Adenovirus and Epstein-Barr virus

Striking similarities are exhibited by two small Epstein-Barr virus-encoded ribonucleic acids and the adenovirus-associated ribonucleic acids VAI and VAII. MD Rosa, E Gottlieb, MR Lerner, JA Steitz. Mol Cell Biol 1981 Sep;1(9):785-796. "VAII RNA as well as VAI RNA and the EBERs exist in ribonucleoprotein complexes which are precipitable by anti-La antibodies associated with systemic lupus erythematosus."

Rosa - Mol Cell Biol 1981 full article / PubMed Central

Two small RNAs encoded by Epstein-Barr virus can functionally substitute for the virus-associated RNAs in the lytic growth of adenovirus 5. RA Bhat, B Thimmappaya. Proc Natl Acad Sci USA 1983 Aug;80(15):4789-4793. "To examine whether the EBRs can functionally substitute for the VA RNAs for the lytic growth of Ad5, we have constructed an Ad5 substitution mutant in which the two VA RNA genes have been deleted and replaced by an EBV DNA segment coding for the two EBERs. The resulting Ad5 mutant synthesizes large amounts of the EBERs and is viable."

Bhat / PNAS 1983 full article
Bhat - PNAS 1983 full article / PubMed Central

Construction and analysis of additional adenovirus substitution mutants confirm the complementation of VAI RNA function by two small RNAs encoded by Epstein-Barr virus. RA Bhat, B Thimmappaya. J Virol 1985 Dec;56(3):750-756. "Adenovirus VAI RNA is essential for the efficient initiation of translation of viral mRNAs at late times after infection. Recently, by constructing an adenovirus type 5 substitution mutant, we showed that the Epstein-Barr virus encoded two small RNAs complemented for the VAI RNA function in the adenovirus type 5 lytic growth (Bhat and Thimmappaya, Proc. Natl. Acad. Sci. USA 80:4789-4793, 1983)... Our results convincingly demonstrated that the two Epstein-Barr virus-encoded RNAs can efficiently complement for the VAI RNA-mediated translational defect in adenovirus-infected cells."

Bhat - J Virol 1985 full article / PubMed Central

Adenoviruses evade the immune system

E3/19K from adenovirus 2 is an immunosubversive protein that binds to a structural motif regulating the intracellular transport of major histocompatibility complex class I proteins. WA Jefferies, HG Burgert. J Exp Med 1990 Dec 1;172(6):1653-1664. "A set of hybrid molecules between Kd and Kk were used to localize the regions in major histocompatibility complex (MHC) molecules that are important for their intracellular transport and to further localize the structures responsible for binding to the adenovirus 2 E3/19K protein. This protein appears to be an important mediator of adenovirus persistence. It acts by binding to the immaturely glycosylated forms of MHC class I proteins in the endoplasmic reticulum (ER), preventing their passage to the cell surface and thereby reducing the recognition of infected cells by virus- specific T cells. We find the surprising result that intracellular transport and E3/19K binding are controlled primarily by the first half of the second domain of Kd, thus localizing these phenomena to the five polymorphic residues in this region of the Kd protein."

Jefferies - J Exp Med 1990 full article / PubMed Central
Jefferies / J Exp Med 1990 Full Article

Adenovirus infection inhibits the phosphorylation of major histocompatibility complex class I proteins. R Lippe, E Luke, YT Kuah, C Lomas, WA Jefferies. J Exp Med 1991 Nov 1;174(5):1159-1166.

Lippe - J Exp Med 1991 full article / PubMed Central
Lippe / J Exp Med 1991 Full Article

Specific inhibition of interferon signal transduction pathways by adenoviral infection. TD Joseph, DC Look. J Biol Chem 2001 Dec 14;276(50):47136-47142.

Joseph / J Biol Chem 2001 full article

The adenovirus E3 RID Complex Protects Some Cultured Human T and B Lymphocytes from Fas-Induced Apoptosis. AL McNees, CT Garnett, LR Gooding. J Virol 2002 Oct 1;76(19):9716-9723. "This study demonstrates that the E3 RID complex protects lymphocytes from apoptosis induced by signaling through the Fas receptor and that this protection may depend upon the stage of differentiation of the lymphocyte. This in turn suggests that in natural Ad infection, persistently or latently infected lymphocytes may enjoy preferential survival due to blockade of normal apoptotic signals."

McNees / J Virol 2002 Full Article
McNees - J Virol 2002 Full Article / PubMed Central

New Strains of Adenovirus Emerge and Spread

"The emergence and apparent global spread of Ad7d2 are reminiscent of observations for another genome type of serotype 7, Ad7b. Originally described by Wadell and Varsanyi, Ad7b was associated with outbreaks of severe respiratory illness in Europe in the 1970s. Although first isolated in 1956 from a Paris orphanage outbreak, subsequent retrospective studies did not identify Ad7b in Europe again until 1969. Before then, the earliest documented occurrence of Ad7b was in China in 1958, where it was the predominant genome type circulating throught the early 1980s. With the exception of Paris, the first emergence of Ad7b outside China was on the US West Coast in 1962. By 1970, Ad7b was the predominant genome type circulating throughout the United States and eventually throughout many parts of the world." (Molecular epidemiology of adenovirus type 7 in the United States, 1966-2000. DD Erdman, W Xu, SI Gerber, GC Gray, D Schnurr, AE Kajon, LJ Anderson. Emerg Infect Dis 2002;8(3)./Medscape.)

Erdman / EID-Medscape 2002

Adenovirus Overview

Adenoviruses, By Dr Alan Cann. MicrobiologyBytes.

Adenoviruses / MicrobiologyBytes

Merkel Cell Polyomavirus Is Implicated in Lung Cancer

Ultrastructural proof of polyomavirus in Merkel cell carcinoma tumour cells and its absence in small cell carcinoma of the lung. CT Wetzels, JG Hoefnagel, JM Bakkers, HB Dijkman, WA Blokx, WJ Melchers. PLoS ONE 2009;4(3):e4958. MCPyV was found in 2/5 Merkel cell carcinomas and 0/10 small cell lung carcinomas.

Wetzels / PLoS ONE 2009 full article
Wetzels - PLoS ONE 2009 full article / PubMed Central

Merkel cell polyomavirus strains in patients with merkel cell carcinoma. A Touzé, J Gaitan, A Maruani, E Le Bidre, A Doussinaud, C Clavel, A Durlach, F Aubin, S Guyétant, G Lorette, P Coursaget. Emerg Infect Dis 2009 Jun;15(6):960-962. 21 of 32 (66%) samples of Merkel cell carcinoma with suitable quality DNA were positive for Merkel cell polyomavirus DNA. All 12 frozen samples were positive versus only 9/20 (45%) of formalin-fixed and paraffin-embedded samples. "MCPyV DNA was not detected for any of the 9 patients with non-MCC neuroendocrine carcinomas," which were 5 small-cell lung carcinomas, 3 well-differentiated intestinal carcinomas, and 1 high-grade neuroendocrine carcinoma of the cervix.

Touzé / Emerg Infect Dis 2009 full article

Frequent hypermethylation of RASSF1A tumour suppressor gene promoter and presence of Merkel cell polyomavirus in small cell lung cancer. P Helmbold, C Lahtz, E Herpel, PA Schnabel, RH Dammann. Eur J Cancer 2009 Aug;45(12):2207-2211. "18 SCLCs (14 primaries and 4 regional lymph node metastases) and 18 blood control samples. MCPyV was found in 39% (7 of 18) of the tumour tissues but not observed in controls. SV40 was not observed in the tumour tissue." "RASSF1A promoter hypermethylation (94%; 17 of 18) was more frequent compared to p16 methylation (56%, 10 of 18). We found no significant correlation between RASSF1A or p16 promoter hypermethylation and infection with the investigated polyoma viruses."

Helmbold - Eur J Cancer 2009 abstract / PubMed

Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. KJ Busam, AA Jungbluth, N Rekthman, D Coit, M Pulitzer, J Bini, R Arora, NC Hanson, JA Tassello, D Frosina, P Moore, Y Chang. Am J Surg Pathol 2009 Sep;33(9):1378-1385. 15 of 17 (88%) frozen Merkel cell carcinoma samples were positive for MCV by PCR. "A tissue microarray of 36 MCCs, 7 combined squamous and neuroendocrine carcinomas of the skin, and 26 pulmonary neuroendocrine carcinomas were also examined by IHC. Of the 36 MCCs assembled on a microarray, 32 (89%) tumors expressed CK20, and 27 (75%) were immunoreactive with CM2B4. The skin tumors with a combined squamous and neuroendocrine phenotype and all pulmonary neuroendocrine carcinomas failed to react with CM2B4."

Busam - Am J Surg Pathol 2009 abstract / PubMed

Merkel cell polyomavirus is prevalent in a subset of small cell lung cancer: a study of 31 patients. C Andres, S Ihrler, U Puchta, MJ Flaig. Thorax 2009 Nov;64(11):1007-1008. Letter.

Andres / Thorax 2009 extract

Detection of Merkel cell polyomavirus in Merkel cell carcinomas and small cell carcinomas by PCR and immunohistochemistry. HS Jung, YL Choi, JS Choi, JH Roh, JK Pyon, KJ Woo, EH Lee, KT Jang, J Han, CS Park, YS Park, YK Shin. Histol Histopathol 2011 Oct;26(10):1231-1241. 14 MCCs, 24 SCCs, 7 Ewing sarcoma/primitive neuroectodermal tumors (ES/PNETs) and 5 neuroblastomas; and a variety of other cancers. "In total, 12 of 14 (85.7%) MCC cases were positive for MCPyV by PCR, which was consistent with published data. Some SCC specimens were also positive for MCPyV (37.5%) by PCR. PCR products from MCC and SCC cases showed premature truncation and frameshift mutation. Furthermore, one case of ES/PNET and one gastric carcinoma showed MCPyV DNA. However, MCPyV DNA and transcript were only detected in MCCs with quantitative real-time PCR analysis. In addition, 11 of 13 (84.6%) MCC cases and 6 of 23 (26.1%) SCC cases showed immunoreactivity with monoclonal antibodies against MCPyV large T-antigen. Considering both PCR and IHC results, MCPyV was detected in all MCCs tested. The presence of MCPyV in all MCC cases tested and in some SCC cases suggests that MCPyV may be involved in the malignant transformation."

Jung - Histol Histopathol 2011 abstract / PubMed

The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites. TY Ly, NM Walsh, S Pasternak. Hum Pathol 2012 Apr;43(4):557-566. "Merkel cell polyomavirus large T antigen was detected in 17 (63%) of 27 pure Merkel cell carcinomas and absent in all 15 (0%) combined Merkel cell carcinomas. Furthermore, complete concordance (100%) of Merkel cell polyomavirus large T antigen expression was observed in 10 cases of primary Merkel cell carcinoma and subsequent tumor metastases. We also evaluated 70 non-Merkel cell carcinoma lesions including 15 cases each of pulmonary and gastrointestinal neuroendocrine tumors. All 70 non-Merkel cell carcinoma lesions were negative for Merkel cell polyomavirus by CM2B4 immunohistochemistry, irrespective of any known Merkel cell carcinoma diagnosis and immune status."

Ly - Hum Pathol 2012 abstract / PubMed

Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA. D de Biase, M Ragazzi, S Asioli, V Eusebi. Hum Pathol 2012 Jul;43(7):980-985. "Cases studied were 5 primary Merkel cell carcinomas in lymph nodes, 1 in the parotid gland, and 12 in the skin. Twelve cases of primary and metastatic small cell carcinoma of the lung were also investigated... Cytokeratin 20 and Merkel cell polyomavirus were detected in all cases of primary Merkel cell carcinoma irrespective of their site of origin. On the contrary, all cases of pulmonary small cell carcinoma were negative for both Merkel cell polyomavirus and cytokeratin 20."

de Biase - Hum Pathol 2012 abstract / PubMed

Detection of Merkel cell polyomavirus with a tumour-specific signature in non-small cell lung cancer. Y Hashida, M Imajoh, Y Nemoto, M Kamioka, A Taniguchi, T Taguchi, M Kume, K Orihashi, M Daibata. Br J Cancer 2013 Feb 19;108(3):629-637. 112 non-small cell lung cancers. "PCR revealed that 9 out of 32 squamous cell carcinomas (SCCs), 9 out of 45 adenocarcinomas (ACs), 1 out of 32 large-cell carcinomas, and 1 out of 3 pleomorphic carcinomas were positive for MCPyV DNA. Some MCPyV DNA-positive cancers expressed large T antigen (LT) RNA transcripts. Immunohistochemistry showed that MCPyV LT antigen was expressed in the tumour cells. The viral integration sites were identified in one SCC and one AC. One had both episomal and integrated/truncated forms. The other carried an integrated MCPyV genome with frameshift mutations in the LT gene."

Hashida - Br J Cancer 2013 abstract / PubMed

The presence of Merkel cell polyomavirus is associated with deregulated expression of BRAF and Bcl-2 genes in non-small cell lung cancer. I Lasithiotaki, KM Antoniou, SP Derdas, E Sarchianaki, EK Symvoulakis, A Psaraki, DA Spandidos, EN Stathopoulos, NM Siafakas, G Sourvinos. Int J Cancer 2013 Aug 1;133(3):604-611. Biopsies from 110 patients with primary NSCLC and 14 from healthy tissue. 10/110 (9.1%) were positive for the presence of MCPyV DNA versus zero controls. "The MCPyV-positive samples were predominantly obtained from male smokers (9/10). BKV and JCV DNA were not detected either in lung tissues biopsies or the control specimens. Interestingly, gene expression analysis revealed increased mRNA and protein expression of BRAF gene in association with BRAF phosphorylation in the MCPyV-positive samples, whereas Bcl-2 gene expression was downregulated in the same type of samples."

Lasithiotaki - Int J Cancer 2013 abstract / PubMed

Association of Merkel cell polyomavirus infection with EGFR mutation status in Chinese non-small cell lung cancer patients. S Xu, J Jiang, X Yu, D Sheng, T Zhu, M Jin. Lung Cancer 2014 Mar;83(3):341-346. 189 non-small cell lung cancer samples. "Thirty out of 163 adenocarcinoma and 2 out of 18 squamous cell carcinoma were found to have MCPyV LT DNA by PCR. Immunostaining also showed LT protein expression in most of the DNA positive samples. EGFR mutations were more frequently detected in female (P=0.009) and non-smoking patients (P=0.0001). Furthermore, a significant association between MCPyV infection and EGFR mutations was found (P=0.001)."

Xu - Lung Cancer 2014 abstract / PubMed

No evidence for a role of Merkel cell polyomavirus in small cell lung cancer among Iranian subjects. S Karimi, F Yousefi, S Seifi, A Khosravi, SA Nadji. Pathol Res Pract 2014 Dec;210(12):836-839. No MCPyV DNA was found among 50 SCLC and 29 non-SCLC patients.

Karimi - Pathol Res Pract 2014 abstract / PubMed

Merkel Cell Polyomavirus is Not Detected in Lung Adenocarcinomas by Immunohistochemistry. HE Trejo Bittar, L Pantanowitz. Appl Immunohistochem Mol Morphol 2016 Jul;24(6):427-430. 0 out of 90 lung adenocarcinomas were positive for MCPyV T antigen expression by immunohistochemistry.

Trejo Bittar - Appl Immunohistochem Mol Morphol 2015 abstract / PubMed

Clinical and prognostic significance of Merkel cell polyomavirus in nonsmall cell lung cancer. GJ Kim, JH Lee, DH Lee. Medicine (Baltimore) 2017 Jan;96(3):e5413. 92 squamous cell carcinomas and 75 adenocarcinomas. MCPyV DNA was detected in 30 patients (18.0%) out of 167.

Kim - Medicine (Baltimore) 2017 abstract / PubMed

Evaluation of Merkel cell polyomavirus in non-small cell lung cancer and adjacent normal cells. A Behdarvand, MS Zamani, F Sadeghi, Y Yahyapour, F Vaziri, FR Jamnani, B Nowruzi, A Fateh, SD Siadat. Microb Pathog 2017 Jul;108:21-26. 96 patients. "Of the 42 ADs, MCPyV DNA was determined in 15 (35.7%) samples and of the 54 SCC, MCPyV DNA was detected in 22 (40.7%) samples. Only one non-cancerous sample in SCC subjects was positive for MCPyV LT-Ag DNA load (0.216 × 10-3)."

Behdarvand - Microb Pathog 2017 abstract / PubMed

Detection of Merkel Cell Polyomavirus in Respiratory Tract Specimens. E Shikova, D Emin, D Alexandrova, M Shindov, A Kumanova, A Lekov, U Moens. Intervirology 2017;60(1-2):28-32. No MCPyV DNA was found in an unknown number of lung cancers.

Shikova - Intervirology 2017 abstract / PubMed

Survey of KI, WU, MW, and STL Polyomavirus in Cancerous and Non-Cancerous Lung Tissues. E Csoma, L Bidiga, G Méhes, M Katona, L Gergely. Pathobiology 2017 Sep 29 [Epub ahead of print]. 100 cancerous and 47 non-cancerous samples. "Neither of the viruses was found in samples from small-cell, non-small-cell (adenocarcinoma, squamous-cell carcinoma and large-cell neuroendocrine lung cancer), mixed-type and non-differentiated lung carcinoma, and non-cancerous lung tissues (from patients with pneumonia, emphysema and fibrosis)."

Csoma - Pathobiology 2017 abstract / PubMed


Merkel cell polyomavirus DNA in respiratory specimens from children and adults. S Bialasiewicz, SB Lambert, DM Whiley, MD Nissen, TP Sloots. Emerg Infect Dis 2009 Mar;15(3):492-494. "Merkel cell polyomavirus (MCPyV) DNA was detected in 7 (1.3%) of 526 respiratory tract samples from patients in Australia with upper or lower respiratory tract symptoms. Partial T antigen and major capsid protein sequences of MCPyV identified in respiratory secretions showed high homology (99%-100%) to those found in Merkel cell carcinoma."

Bialasiewicz / Emerg Infect Dis 2009 full article
Bialasiewicz - Emerg Infect Dis 2009 full article / PubMed Central

Merkel cell polyomavirus DNA in tumor-free tonsillar tissues and upper respiratory tract samples: Implications for respiratory transmission and latency. K Kantola, M Sadeghi, A Lahtinen, M Koskenvuo, LM Aaltonen, M Möttönen, J Rahiala, U Saarinen-Pihkala, P Riikonen, T Jartti, O Ruuskanen, M Söderlund-Venermo, K Hedman. J Clin Virol 2009 Aug;45(4):292-295. "Altogether 1390 samples from immunocompetent or immunocompromised patients, including (i) tonsillar tissues and sera from tonsillectomy patients; (ii) nasopharyngeal aspirates (NPAs) and sera from wheezing children and (iii) nasal swabs, sera and stools from febrile leukemic children were studied for MCPyV. The tonsils, nasal swabs and stools were also studied for KIPyV and WUPyV. RESULTS: MCPyV DNA was detected in 14 samples altogether; 8 of 229 (3.5%) tonsillar tissues, 3 of 140 (2.1%) NPAs, 2 of 106 (1.9%) nasal swabs and 1 of 840 (0.1%) sera. WUPyV and KIPyV were detected in 5 (2.2%) and 0 tonsils, 1 (0.9%) and 4 (3.8%) nasal swabs and 0 and 2 (2.7%) fecal samples, respectively. The patients carrying in tonsils MCPyV were of significantly higher age (median 42years) than those carrying WUPyV (4years, p<0.001). CONCLUSIONS: MCPyV DNA occurs in tonsils more frequently in adults than in children. By contrast, WUPyV DNA is found preferentially in children. MCPyV occurs also in nasal swabs and NPAs, in a frequency similar to that of KIPyV and WUPyV. The tonsil may be an initial site of WUPyV infection and a site of MCPyV persistence."

Kantola - J Clin Virol 2009 abstract / PubMed


A specific signature of Merkel cell polyomavirus persistence in human cancer cells. H zur Hausen. Proc Natl Acad Sci USA. 2008 Oct 21;105(42):16063-16064. Mutations in the helicase part of the large T antigen of MCpyV result in replication incompetence. These types of mutation in other polyomaviruses have been shown to increase their transformation potential.

zur Hausen / Proc Natl Acad Sci USA 2008 full article

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. M Shuda, H Feng, HJ Kwun, ST Rosen, O Gjoerup, PS Moore, Y Chang. Proc Natl Acad Sci USA 2008 Oct 21;105(42):16272-16277. "Nine MCC tumor-derived LT genomic sequences have been examined, and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation." The mutations "do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity." "Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-positive MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a "passenger virus" that secondarily infects MCC tumors."

Shuda / Proc Natl Acad Sci USA 2008 full article
Shuda - Proc Natl Acad Sci USA 2008 full article / PubMed Central

Aberrant expression of miR-21, miR-376c and miR-145 and their target host genes in Merkel cell polyomavirus-positive non-small cell lung cancer. I Lasithiotaki, E Tsitoura, A Koutsopoulos, E Lagoudaki, C Koutoulaki, G Pitsidianakis, DA Spandidos, NM Siafakas, G Sourvinos, KM Antoniou. Oncotarget 2016 Aug 11. 8/24 consecutive patients were MCPyV+. "Overall, miR-21 and miR-376c expression was higher in tumour compared to healthy tissue samples."

Lasithiotaki / Oncotarget 2016 full article

See also:

EBV Causes Lymphoepithelioma-Like Lung Cancer
HPV Causes Lung Cancer
Confounding By Infection
The Lie That p53 Mutations Are the Mechanism Behind Lung Cancer
Merkel Cell Polyomavirus Causes Skin Cancer


cast 10-27-17