JC Polyoma Virus Causes Colon Cancer

Hereditary (familial) cancers comprise only about 5-10% of all colorectal cancers. Of the non-hereditary cancers, only 10-15% are associated with microsatellite instability (MSI), while 80-90% are chromosomally mutated (microsatellite-stable, or MSS). Laghi et al. have identified JC virus in 89% of these cancers of the most common, non-MSI type. The viral load is at least ten times higher in the cancers than in normal colon tissue. The polyoma virus T antigen is known to interfere with the p53 tumor suppressor and pRb retinoblastoma proteins to produce cancer in animals.

"We and others have found evidence for chromosomal instability in the earliest stages of colorectal neoplasia, as chromosomal deletions may be found in even tiny, benign colorectal adenomas. Whatever mechanism is responsible for the appearance of this type of genomic instability, it must occur very early in the process and account for both the unbalanced mitoses and the evasion of cell cycle checkpoint control. An infection that introduced the T antigen could explain the abrupt onset of chromosomal instability in multistep carcinogenesis, and we now have evidence that JCV can be present in human colons."

In addition, the study strongly suggests that PCR detection of JC virus in the past has been inadequate. The detection rate improved from 26% to 89% after treatment to uncoil the viral DNA. "In a preliminary study of a group of DNA samples extracted from 23 pairs of normal colorectal epithelium and adjacent cancers, we ran a total of 198 amplifications of the 520-bp target (an average of approximately four PCRs per DNA sample), and 16 of these (8%) were positive. Overall, 12 of the samples (26%) yielded at least one positive amplification of JCV by PCR (Table 1). The PCR products were documented as authentic JCV sequences by Southern blot analysis... The relatively low yield from amplification of the 520-bp sequence led to the hypothesis that the physical configuration of the viral DNA may be important in permitting its efficient amplification. Therefore, primers for the previously described 120- and 93-bp targets were developed. These smaller PCR targets were more readily amplified than the longer sequence (data not presented). The improved yield of positives obtained by amplifying shorter target sequences led us to a consideration of developing technical improvements in methodology for identifying JCV DNA by PCR.... SV40 contains a supercoiled DNA genome, a feature that produced unexpected biochemical characteristics when it was first studied in 1963. We hypothesized that a supercoiled topology of the highly homologous JCV DNA might limit the efficiency of PCR amplification and used topoisomerase I treatment to determine whether the relaxation of supercoiling would improve our yield (which we refer to as topoisomerase I-sensitive polyomavirus amplification, or TISPA). In a series of 54 new DNA samples from normal colons and cancer specimens, TISPA was found to enhance the sensitivity of detection, resulting in the amplification of the 520-bp JCV sequence from 89% of the samples." (JC virus DNA is present in the mucosa of the human colon and in colorectal cancers. L Laghi, AE Randolph, DP Chauhan, G Marra, EO Major, JV Neel, CR Boland. Proc Natl Acad Sci 1999 Jun;96:7484-7489.)

(The establishment's lame denials and understatements of the strength of the evidence): Commentary: Convicting a human tumor virus: Guilt by association? JA Blaho, SA Aaronson. Proc Natl Acad Sci 1999 Jul;96:7619-7621. It is not even up to date about hepatitis B X protein, or human papillomavirus E6; and the so-called investigation of adenovirus 12 has been perfunctory. But most despcable of all is the whining about blaming a virus supposedly only on "guilt by association." The health establishment eagerly convicts tobacco on the strength of nothing but association, purposely deceiving the public with their old bogyman of "carcinogens" when they still have no mechanism of tobacco carcinogenesis, after more than 40 years of pouring the nation's resources into it.

Commentary: How many mutations does it take to make a tumor? CR Boland, L Ricciardiello. Proc Natl Acad Sci 1999 Dec 31;96(26):14675-14677. "In this issue of PNAS, Stoler and colleagues report that typical sporadic colon cancers on average contain at least 11,000 genomic alterations per cell. Furthermore, they report that the genomic instability responsible for generating this number of mutations starts very early in the neoplastic process and can be found in adenomatous polyps, which are known to be the precursors of cancer in the colon and rectum. Should this conclusion be emblazoned on the front page of the evening news, or does this serve to confirm and extend concepts that we already accept?... What mechanisms might account for genomic instability in non-MSI cancers?..."

Mutations of the p53 gene don't occur until after the adenoma becomes malignant: "Thus it occurs too late to account for CIN in benign neoplasms...." "A recent candidate with the ability to create chromosomal instability in human epithelial cells is the T antigen, which is a complex transforming viral gene found in the SV40 virus and in two human viruses: JC virus and BK virus. The work of Hahn et al. indicates that T antigen is a candidate-transforming gene in a human cell model, and work from our group has recently demonstrated that JC viral sequences are present in normal human colons, in colon cancers, and in one colon cancer cell line with CIN...."

JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. L Ricciardiello, L Laghi, P Ramamirtham, CL Chang, DK Chang, AE Randolph, CR Boland. Gastroenterology 2000 Nov;119(5):1228-1235. JCV sequences were found in 75.8% of patients.

Mad-1 is the exclusive JC virus strain present in the human colon, and its transcriptional control region has a deleted 98-base-pair sequence in colon cancer tissues. L Ricciardiello, DK Chang, L Laghi, A Goel, CL Chang, CR Boland. J Virol 2001 Feb;75(4):1996-2001.

Association of human polyomavirus JCV with colon cancer: evidence for interaction of viral T-antigen and beta-catenin. S Enam, L Del Valle, C Lara, DD Gan, C Ortiz-Hidalgo, JP Palazzo, K Khalili. Cancer Res 2002 Dec 1;62(23):7093-7101. The viral early genome was found in 22/27 samples (81%), and T-antigen was found in more than 50%.

No evidence of an association of JC virus and colon neoplasia. PA Newcomb, AC Bush, GL Stoner, JW Lampe, JD Potter, J Bigler. Cancer Epidemiol Biomarkers Prevent 2004 Apr;13(4):662-666.

Constraints imposed by supercoiling on in vitro amplification of polyomavirus DNA. L Laghi, AE Randolph, A Malesci, CR Boland. J Gen Virol 2004 Nov;85(11):3383-3388. "It was found that detection of circular templates required 10 times more molecules than detection of identical but linear templates. Supercoiling hindered the in vitro amplification of SV40 circles by a factor of 10, and erratic amplification of supercoiled SV40 occurred with subpicogram amounts of template. Accordingly, topoisomerase I treatment of DNA improved the PCR detection of supercoiled SV40, significantly decreasing the number of false-negative samples. Previously described, yet controversial, polyomavirus presence in human tissues should be reconsidered and topoisomerase I-sensitive polyomavirus amplification might help to detect polyomavirus genomes in mammalian tissues."

Evidence for an association between JC virus and colorectal neoplasia (letter). CR Boland. Cancer Epidemiol Biomarkers Prevent 2004 Dec;13(12):2285-2286. "Essentially, Newcomb et al. have attempted to use an assay that had not undergone appropriate, relevant validation and speculated that their failure to obtain PCR products refutes multiple lines of evidence from other laboratories. A BLAST analysis indicates that the T-antigen primers in this study form multiple primer dimers which would almost certainly limit the PCR efficiency. Moreover, other primers were found to have complete sequence matches with BK virus as well as JCV suggesting that the primer design was not optimal."

Assessment of JC polyoma virus in colon neoplasms. G Theodoropoulos, D Panoussopoulos, I Papaconstantinou, M Gazouli, M Perdiki, J Bramis, ACh Lazaris. Dis Colon Rectum 2005 Jan;48(1):86-91. 80 cancerous, 25 adenomatous specimens of large bowel, and 20 colonoscopic biopsy samples from normal patients without colorectal neoplasia. "RESULTS: JC polyoma virus nucleotide sequence was detected in 61 percent of colon adenocarcinomas and in 60 percent of adenomas, at a viral load of 9 x 10(3) to 20 x 10(3) copies/microg DNA. Adjacent normal mucosa in 35 positive colon adenocarcinoma specimens, and normal mucosa from six patients of the control group, had low viral loads (50-450 copies/microg DNA)."

C. Richard Boland, M.D., chief of gastroenterology at Baylor Health Care System, Dallas, National Cancer Institute research grant: JC Virus and Tumor Formation in the Human Colon. Grant Number: 1R01CA098572-01A2. Project Start: April 1, 2004; Project End: March 31, 2009. "In this application, we propose to rigorously test the hypothesis that the expression of JCV T-antigen correlates with the stabilization of beta-catenin, the later loss of APC, and the initiation of CIN by studying resected specimens of colorectal neoplasia. Second, we propose to determine whether the integration of the virus into the human genome is necessary for expression of T-antigen and the induction of CIN, using both surgically resected tissues and in vitro approaches. Third, we propose to use our in vitro models of JCV infection to study the time course of immortalization and transformation. Finally, we propose to test the hypothesis that rearrangements in the TCR of JCV provide a mechanism whereby a latent infection is converted into an active one, leading to expression of the viral genes. The implication of this work is that JCV, which is commonly present in the gastrointestinal tract of the majority of healthy humans, may be involved in the initiation of CIN, and colon cancer. If this virus plays a mechanistic role in human carcinogenesis, this could lead to novel preventive and treatment strategies." (Baylor Research Institute Awarded $1.3 Million NIH Grant to Study Possible Viral Role in Colon Cancer. Baylor Research Institute News, April 8, 2004.)

Presence and incidence of DNA sequences of human polyomaviruses BKV and JCV in colorectal tumor tissues. B Casini, L Borgese, F Del Nonno, G Galati, L Izzo, M Caputo, R Perrone Donnorso, M Castelli, G Risuleo, P Visca. Anticancer Res 2005 Mar-Apr;25(2A):1079-1085. Viral DNA sequences were present in 16 out of 18 cases (88.9%) of colorectal carcinomas.

Detection of JC virus DNA sequences in colorectal cancers in Japan. R Hori, Y Murai, K Tsuneyama, HO Abdel-Aziz, K Nomoto, H Takahashi, CM Cheng, T Kuchina, BV Harman, Y Takano. Virchows Arch 2005 Oct;447(4):723-730. "T antigen was detected in 6 of 23 colorectal cancers (26.1%) and 1 of 21 adenomas (4.8%), but none of 20 samples of normal colonic mucosa. No clear and diffuse staining with anti-T-antigen antibodies (1:100) could be detected, and there was no correlation with CD20-positive cells, which might have indicated JCV latent infection of B lymphocytes."

Association of JC virus T-antigen expression with the methylator phenotype in sporadic colorectal cancers. A Goel, MS Li, T Nagasaka, SK Shin, F Fuerst, L Ricciardiello, L Wasserman, CR Boland. Gastroenterology 2006 Jun;130(7):1950-1961. "JCV T-Ag DNA sequences were found in 77% of the CRCs and 56% of these cancers (or 43% of the total) expressed T-Ag by IHC. Significant associations were observed between T-Ag expression and CIN in CRCs (P = .017) and between T-Ag expression and promoter methylation of multiple genes (P = .01)."

JC virus T-antigen expression in sporadic adenomatous polyps of the colon. WT Jung, MS Li, A Goel, CR Boland. Cancer 2008 Mar 1;112(5):1028-1036. "JCV T-Ag sequences were found in 82% (61 of 74) of adenomas, and T-Ag protein was expressed in 16% (12 of 74) of these polyps. The T-Ag staining was localized exclusively in the nuclei of adenoma cells, but never in the cytoplasm or the adjacent nonneoplastic cells. The prevalence of MSI-H and non-MSI-H (MSI-L/MSS) in adenomatous polyps was 9.5% (7 of 74) and 90.5% (67 of 74), respectively. Among the 61 adenomas that harbored JCV sequences, 8% (5 of 61) were MSI-H, and similarly among 12 adenomatous polyps expressing T-Ag protein 8% (1 of 12) of the adenomatous polyps were MSI-H. CONCLUSIONS.: JCV T-Ag DNA sequences are frequently present in adenomatous polyps of the colon, and T-Ag is expressed specifically in the nuclei of these premalignant lesions. This study indicates that JCV T-Ag is present in the early stage of colonic carcinogenesis."

Detection of oncogenic DNA viruses in colorectal cancer. L Giuliani, C Ronci, D Bonifacio, L Di Bonito, C Favalli, CF Perno, K Syrjänen, M Ciotti. Anticancer Res 2008 Mar-Apr;28(2B):1405-1410. Archival tumour samples from 71 patients with colorectal cancer. BKV in 6/66 (9%) of the samples, none contained JCV, SV40 was amplified in 10/66 (15.1%). HPV DNA was detected in 22/66 (33.3%). [These may have been rectal, not colon, cancers.]

Prevalence and genotype identification of human JC virus in colon cancer in Taiwan. PY Lin, CY Fung, FP Chang, WS Huang, WC Chen, JY Wang, D Chang. J Med Virol 2008 Aug 19;80(10):1828-1834. "Nested PCR revealed JCV genomic DNA in 86.4% (19/22) of the colon cancer tissue samples. Both rearranged and archetypal genotypes of JCV were identified. Expression of JCV LT [large tumor protein] was positive in 63.6% (14/22) of the examined colon cancer tissue samples but not in any adjacent normal region."

JC virus infection in colorectal neoplasia that develops after liver transplantation. M Selgrad, JJ Koornstra, L Fini, M Blom, R Huang, EB Devol, W Boersma-van Ek, G Dijkstra, RC Verdonk, S de Jong, A Goel, SL Williams, RL Meyer, EB Haagsma, L Ricciardiello, CR Boland. Clin Cancer Res 2008 Oct 15;14(20):6717-6721. "JCV TAg DNA was found in 10 of 15 (67%) of normal colonic mucosa from LTRs compared with 5 of 21 (24%) of control normal mucosa (P = 0.025). JCV TAg DNA was detected in 16 of 26 (62%) of the adenomas from LTRs and in 20 of 40 (50%) of control adenomas. JCV TAg protein was expressed in 13 of 26 (50%) adenomas from LTRs versus 2 of 40 (5%) of adenomas from controls (P < 0.001)."

Mechanisms of transformation

Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. L Ricciardiello, M Baglioni, C Giovannini, M Pariali, G Cenacchi, A Ripalti, MP Landini, H Sawa, K Nagashima, RJ Frisque, A Goel, CR Boland, M Tognon, E Roda, F Bazzoli. Cancer Res 2003 Nov 1;63(21):7256-7562. "In conclusion, we demonstrate that JC virus Mad-1 and [delta]98 are able to induce chromosomal instability in colonic cells with a hit and run mechanism that involves an early interaction with β-catenin and p53."

Role of JC virus agnoprotein in DNA repair. A Darbinyan, KM Siddiqui, D Slonina, N Darbinyan, S Amini, MK White, K Khalili. J Virology 2004 Aug;78(16):8593-8600. "[A]gnoprotein expression sensitized cells to the cytotoxic effects of the DNA-damaging agent cisplatin."

JC virus and colorectal cancer: a possible trigger in the chromosomal instability pathways. Y Niv, A Goel, CR Boland. Curr Opin Gastroenterol 2005 Jan; 21(1):85-89. "In people who develop colorectal neoplasia, it is proposed that the virus is activated, and expression of the oncogene-T-antigen-leads to CIN. This form of genomic instability is necessary to explain the losses of tumor suppressor genes that occur in the context of the multistep carcinogenesis pathway. Furthermore, it is proposed that once neoplastic colonic epithelial cells have experienced biallelic inactivation of a critical number of tissue-specific tumor suppressor genes-including APC and p53-the ongoing effect of the transforming virus may be relatively deleterious to a neoplastic cell, and selective pressure may lead to loss of viral infection. SUMMARY: This review summarizes the experimental data that have led to the hypothesis that JCV is a common cause of CIN in CRC [colorectal cancer]."

Infection and the APC gene in colon cancer

Bacterial infection promotes colon tumorigenesis in Apc(Min/+) mice. JV Newman, T Kosaka, BJ Sheppard, JG Fox, DB Schauer. J Infect Dis 2001 Jul 15;184(2):227-230. "The Min mouse, which has a germ line mutation in 1 allele of the Apc tumor suppressor gene, is a model for the early steps in human colorectal cancer... Infection with the bacterium Citrobacter rodentium is known to increase epithelial cell proliferation and to promote chemically initiated tumors in the colon of mice."

A possible role of CMV

Cytomegalovirus D.N.A. and adenocarcinoma of the colon: Evidence for latent viral infection. ES Huang, JK Roche. Lancet 1978 May 6;1(8071):957-960. "4 of 7 tumours of the colon were definitely positive for C.M.V. D.N.A."

Human cytomegalovirus and human herpesvirus 6 genes that transform and transactivate. J Doniger, S Muralidhar, LJ Rosenthal. Clinical Microbiology Reviews 1999 Jul;12(3):367-382.

Enhanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon. KN Khan, JL Masferrer, BM Woerner, R Soslow, AT Koki. Scand J Gastroenterol 2001 Aug;36(8):865-869.

Inhibition of cyclooxygenase 2 blocks human cytomegalovirus replication. H Zhu, JP Cong, D Yu, WA Bresnahan, TE Shenk. Proc Natl Acad Sci 2002 Mar 19;99(6):3932-3937.

A randomized, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. RK Phillips, MH Wallace, PM Lynch, E Hawk, GB Gordon, BP Saunders, N Wakabayashi, Y Shen, S Zimmerman, L Godio, M Rodrigues-Bigas, LK Su, J Sherman, G Keiloff, B Levin, G Steinbach, FAP Study Group. Gut 2002 Jun;50(6):857-860. Found a signficant reduction in area covered by duodenal polyps after six months, in patients with the most disease.

Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. L Harkins, AL Volk, M Samanta, I Mikolaenko, WJ Britt, KI Bland, CS Cobbs. Lancet 2002 Nov 16;360(9345):1557-1563. "In vitro, human cytomegalovirus can transform cells and dysregulate many cellular pathways relevant to colon adenocarcinoma pathogenesis, especially those affecting the cell cycle, mutagenesis, apoptosis, angiogenesis, and cyclo-oxygenase-2 (COX-2) expression... Human cytomegalovirus proteins IE1-72 and pp65 were detected in a tumour cell-specific pattern in 14 (82%) of 17 and seven (78%) of nine colorectal polyps, respectively, and 12 (80%) of 15 and 11 (92%) of 12 adenocarcinomas, respectively, but not in adjacent non-neoplastic colon biopsy samples from the same patients (none of seven and none of two, respectively)." (UAB Scientists Link Cytomegalovirus with Colon Cancer. UAB Health System, posted October 10, 2003. Link died http://www.health.uab.edu/show.asp?durki=62658.)

Cytomegalovirus is not associated with progression and metastasis of colorectal cancer. T Knösel, C Schewe, M Dietel, I Petersen. Cancer Lett 2004 Aug 10;211(2):243-247. "Fresh-frozen biopsy specimens from 77 primary and metastatic colorectal carcinomas of randomly selected patients were analyzed by PCR and immunohistochemistry. We investigated 57 primary tumors and 20 metastases, comprising 13 tumor pairs from the same patient. In PCR, four primary tumors showed a positive CMV result whereas all investigated metastases were negative including three paired samples from positive primaries. In immunohistochemistry, no specific staining could be determined in all neoplastic epithelial cells."

Is cytomegalovirus associated with human colorectal tumorigenesis? O Akintola-Ogunremi, Q Luo, TC He, HL Wang. Am J Clin Pathol 2005 Feb;123(2):244-249. "In 23 colorectal hyperplastic polyps, 65 colorectal adenomas, and 51 colorectal adenocarcinomas, no nuclear positivity was detected by IHC."

Reactivation of infection

Age-Related Urinary Excretion of BK Polyomavirus by Non-immunocompromised Individuals. S Zhong, HY Zheng, M Suzuki,Q Chen, H Ikegaya, N Aoki, S Usuku, N Kobayashi, S Nukuzuma, Y Yasuda, N Kuniyoshi, Y Yogo, T Kitamura. J Clin Microbiol 2007 Jan;45(1):193-198. In 9 age groups of 50 healthy volunteers or non-immunocompromised patients, "The rate of BK viruria was relatively low in subjects aged <30 years old, but gradually increased with age in subjects >/=30 years old. However, BK viruria was less frequent than JC viruria in adults."

The anti-smokers' lies about smoking and colon cancer

"Smoking Ups Gene Defect in Colon Cancer," by Suzanne Rostler. Reuters 2000 Nov 15. This story is serial psychopathic lying. By claiming that "21% of the defect in colon tumors, called microsatellite instability (MSI), can be blamed on cigarette smoking, they mislead the public to believe that smoking is implicated in 21% of colon cancer. But, since only 10-15% of nonhereditary colon cancers are of the MSI type in the first place, this would constitute only 2 to 3%. And, "'Smoking is perhaps the largest contributor to MSI in tumors identified to date,' according to Slattery, from the University of Utah in Salt Lake City, and colleagues." In fact, they haven't identified anything as a causal factor, including smoking.

But one thing that is known is that most MSI, particularly high-frequency MSI (MSI-H), is caused by methylation of the hMLH1 DNA mismatch repair gene which inactivates it, not by the mutation or deletion of this gene. Its activity can be restored in cultured cell lines by a demethylating agent. If the cell lines are left untreated for a couple of weeks, hMLH1 expression slowly declines, but can be restored again by the demethylating agent. This is consistent with the effects of insertion of some viral sequence which produces an inactivating protein. (Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. ML Veigl, L Kasturi, J Olechnowicz, AH Ma, JD Lutterbaugh, S Periyasamy, G-M Li, J Drummond, PL Modrich, WD Sedwick, SD Markowitz. Proc Natl Acad Sci USA 1998 Jul;95(15):8698-8702.)

And Rostler lied that "women who smoked increased their risk of developing these tumors more than 200 times," when the study only claimed an odds ratio of 2.2 (95% confidence interval 1.4-3.5). This is easily within the range of bogus odds ratios generated by confounding by infection, as Slattery ought to know from having her 1989 study pretending that smoking causes cervical cancer knocked into a cocked hat by the unanticipated discovery that HPV causes virtually all cervical cancer.

This study from the American Cancer Society's Cancer Prevention Study II is worthless junk science as well, because it lumps all types of colon cancer together and ignores the confounding role of infection: Cigarette smoking and colorectal cancer mortality in the Cancer Prevention Study II. A Chao, MJ Thun, EJ Jacobs, SJ Henley, C Rodriguez, EE Calle. J Natl Cancer Inst 2000 Dec 6;92(23):1888-1896.

And another batch of lies: "Gene discovery links smoking and colorectal cancer," by Elizabeth Tracey (Reuters Health 2001 Jan 26). It claims that "smokers with a mutation in the alpha-1 anti-trypsin gene were 20 times as likely to develop the subtype of colorectal cancer compared with nonsmokers who did not have the gene mutation." But according to OMIM (the Online Mendelian Inheritance In Man), homozygous alpha-1 anti-trypsin deficiency mutations have not been implicated in colon cancer, and these patients were just carriers. Also, black people have higher rates of MSI colon cancer, yet alpha-1 anti-trypsin mutations are very rare in blacks. The increased rates in both blacks and smokers points to infection as the underlying confounding factor in common. And as usual in anti-smoker studies, in contrast to more reputable studies, they used multivariate analysis to generate bogus risks by confounding, and threw in some empty speculation about "chronic tissue damage" and uncalled-for fear mongering. (Higher risk of mismatch repair-deficient colorectal cancer in alpha(1)-antitrypsin deficiency carriers and cigarette smokers. P Yang, JM Cunningham, KC Halling, TG Lesnick, LJ Burgart, EM Wiegert, ER Christensen, NM Lindor, JA Katzman, SN Thibodeau. Mol Genet Metab 2000 Dec;71(4):639-645.)

Anna Wu of the University of Southern California has received two grants totalling $1,565,774 for "Smoking, microsatellite instability & gastric cancers" and "Smoking and Risk of Proximal Vs. Distal Gastric Cancer." The money comes from the so-called Tobacco-Related Disease Research Program, a vast slush fund for anti-smoker pseudo-science which is funded by smokers' money stolen via California's Proposition 99 cigarette tax.

The health establishment has also poured enormous resources into trying to implicate diet in colon cancer, with paltry results, such as the $625-million Women's Health Initiative Randomized Controlled Dietary Modification Trial:

Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. SA Beresford, KC Johnson, C Ritenbaugh, NL Lasser, LG Snetselaar, HR Black, GL Anderson, AR Assaf, T Bassford, D Bowen, RL Brunner, RG Brzyski, B Caan, RT Chlebowski, M Gass, RC Harrigan, J Hays, D Heber, G Heiss, SL Hendrix, BV Howard, J Hsia, FA Hubbell, RD Jackson, JM Kotchen, LH Kuller, AZ LaCroix, DS Lane, RD Langer, CE Lewis, JE Manson, KL Margolis, Y Mossavar-Rahmani, JK Ockene, LM Parker, MG Perri, L Phillips, RL Prentice, J Robbins, JE Rossouw, GE Sarto, ML Stefanick, L Van Horn, MZ Vitolins, J Wactawski-Wende, RB Wallace, E Whitlock. JAMA 2006 Feb 8;295(6):643-54. "Intervention group participants significantly reduced their percentage of energy from fat by 10.7% more than did the comparison group at 1 year, and this difference between groups was mostly maintained (8.1% at year 6). Statistically significant increases in vegetable, fruit, and grain servings were also made. Despite these dietary changes, there was no evidence that the intervention reduced the risk of invasive colorectal cancer during the follow-up period. There were 201 women with invasive colorectal cancer (0.13% per year) in the intervention group and 279 (0.12% per year) in the comparison group (hazard ratio, 1.08; 95% confidence interval, 0.90-1.29)."

Human Polyomaviruses and Rogue Cells

Cytogenetic "rogue" cells: what is their frequency, origin, and evolutionary significance? AA Awa, JV Neel. Proc Natl Acad Sci USA 1986 Feb;83(4):1021-1025. [dates from before JCV and BKV were implicated.]

High titers of antibodies to two human polyomaviruses, JCV and BKV, correlate with increased frequency of chromosomal damage in human lymphocytes. JR Lazutka, JV Neel, EO Major, V Dedonyte, J Mierauskine, G Slapsyte, A Kesminiene. Cancer Lett 1996 Dec 3;109(1-2):177-183. In 33 workers occupationally exposed to low doses of ionizing radiation and 11 controls, "There were no statistically significant differences in the JC and BK virus titer values between two groups of donors. It was found that JC and BK virus titers explained approximately 6% of total inter-individual variation in CA [chromosome aberration] frequency. Such factors as alcohol abuse, age and, in this special group, exposure to ionizing radiation explained an additional 53% of the total variation in CA frequency. In six clean-up workers and one control, rogue cell (cells with multiple chromosome-type aberrations) were found. The incidence of rogue cells correlated significantly with JC and BK virus titers as well as a history of recent acute respiratory disease."

Hypothesis: "Rogue cell"-type chromosomal damage in lymphocytes is associated with infection with the JC human polyoma virus and has implications for oncopenesis. JV Neel, EO Major, AA Awa, T Glover, A Burgess, R Traub, B Curfman, C Satoh. Proc Natl Acad Sci USA 1996 Apr 2;93(7):2690-2695. "Cultured lymphocytes exhibiting extreme chromosomal damage in the absence of any known cause, which we have termed "rogue" cells, were first encountered in significant numbers in 1968 in studies on two villages of Yanomama Amerindians.... Subsequently, similar cells have been reported in mixed nationality North Sea divers, as well as in the inhabitants of England, Japan, Ukraine, Lithuania, Russia, and Byelorussia.... Especially relevant in the present context is the demonstration more than 30 years ago by Koprowski et al., Yerganian et al., Cooper and Black, and Moorhead and Saksela (16) of extensive cytogenetic abnormalities in human cell lines transformed by a papovavirus, simian virus 40 (SV40)..."

The incidence of cytogenetically abnormal rogue cells in peripheral blood. R Mustonen, C Lindholm, EJ Tawn, L Sabatier, S Salomaa. Int J Radiat Biol 1998 Dec;74(6):781-785. "Rogue cells were found both from controls and from exposed subjects. The highest incidence of these cells was observed in a control group of young trainees (1:400), whereas the lowest incidence of rogue cells (1:36 500) was demonstrated in a follow-up study of people accidentally exposed to high levels of ionizing radiation. Rogue cells were found to be distributed non-randomly among individuals; the highest individual frequency was 1 in 50 analysed metaphases."

An association, in adult Japanese, between the occurrence of rogue cells among cultured lymphocytes (JC virus activity) and the frequency of "simple" chromosomal damage among the lymphocytes of persons exhibiting these rogue cells. JV Neel. Am J Hum Genet 1998 Aug;63(2):489-497. 45 out of 1,835 persons exhibited rogue cells: "Rogue cells are cells with complex chromosomal damage, currently believed to be a manifestation of the activity of a human polyoma virus termed "JC." ... In both the exposed and the control populations, there was an absolute increase of approximately 1.5% in the frequency of simple chromosomal damage in the nonrogue cells of those exhibiting rogue cells [emphasis added], when compared with the frequencies observed in those not exhibiting rogue cells, which is a statistically significant difference. It is argued that this phenomenon, occurring not only in lymphocytes but possibly also in other cells/tissues, may play a contributory role in the origin of malignancies characterized by clonal chromosome abnormalities. Unexpectedly, among those exhibiting rogue cells, there was a disproportionately greater representation of persons who had received relatively high radiation exposures from the bomb."

Geographic variations of JC virus strains

The different strains of JC virus around the world can even be used to trace ancient human migrations. And, perhaps they explain why rates of colon cancer vary widely in different parts of the world.

Typing of urinary JC virus DNA offers a novel means of tracing human migrations. C Sugimoto, T Kitamura, J Guo, MN Al-Ahdal, SN Shchelkunov, B Otuva, P Ondrejka, J-Y Chollet, S El-Safi, M Ettayebi, G Gresenguet, T Kocagoz, S Chaiyarasamee, KZ Thant, S Thein, K Moe, N Kobayashi, F Taguchi, Y Yogo. PNAS 1997 Aug;94(17):9191-9196.

Asian genotypes of JC virus in Native Americans and in a Pacific Island population: Markers of viral evolution and human migration. HT Agostini, R Yanagihara, V Davis, CF Ryschkewitsch, GL Stoner. PNAS 1997 Dec;94(26):14542-14546.

Four geographically distinct genotypes of JC virus are prevalent in China and Mongolia: implications for the racial composition of modern China. J Guo, C Sugimoto, T Kitamura, H Ebihara, A Kato, Z Guo, J Liu, SP Zheng, YL Wang, YQ Na, M Suzuki, F Taguchi, Y Yogo. J Gen Virol 1998;79(10):2499-2505.

Human polyomavirus JC variants in Papua New Guinea and Guam reflect ancient population settlement and viral evolution. CF Ryschkewitsch, JS Friedlaender, CS Mgone, DV Jobes, HT Agostini, SC Chima, MP Alpers, G Koki, R Yanagihara, GL Stoner. Microbes Infect 2000 Jul 1;2(9):987-996.

Genotypes of JC virus in East, Central and Southwest Europe. HT Agostini, A Deckhut, DV Jobes, R Girones, G Schlunck, MG Prost, C Frias, E Perez-Trallero, CF Ryschkewitsch, GL Stoner. J Gen Virol 2001 May;82(Pt 5):1221-1231.

Reconstructing population history using JC virus: Amerinds, Spanish, and Africans in the history of modern Puerto Ricans. MF Cobo, DV Jobes, R Yanagihara, VR Nerurkar, Y Yamamura, CF Ryschkewitsch, GL Stoner. Hum Biol 2001 Jun;73(3):385-402.

New JC virus (JCV) genotypes from Papua New Guinea and Micronesia (type 8 and type 2E) and evolutionary analysis of 32 complete JCV genomes. DV Jobe, JS Friedlander, CS Mgone, HT Agostini, G Koki, R Yanagihara, TCN Ng, SC Chima, CF Ryschkewitsch, GL Stoner. Arch Virol 2001;146(11):2097-2113.

Asian domains of four major genotypes of JC virus, Af2, B1-B, CY and SC. L Saruwatari, C Sugimoto, T Kitamura, N Ohno, E Sakai, P Shresta, BK Hoa, PT Phi, HP An, NT Tuyet, T Honjo, N Kobayashi, HY Zheng, T Takasaki, Y Yogo. Arch Virol 2002;147(1):1-10.

Evolution of human polyomavirus JC: implications for the population history of humans. C Sugimoto, M Hasegawa, A Kato, HY Zheng, H Ebihara, F Taguchi, T Kitamura, Y Yogo. J Mol Evol 2002 Mar;54(3):285-297.

Do adeno-associated viruses cause colon (and/or other) cancer?

Adeno-associated viruses are conventionally described as defective parvoviruses that need a helper virus, such as adenovirus or any herpes virus, in order to replicate. If a helper virus is not available, it integrates into the chromosome, mainly into a certain region of chromosome 19 called AAVS1. Because of this, AAVs are being developed for use as vectors in gene therapy. The PR insists that they are "non-pathogenic." However, this claim is based on superficial observation of lack of acute symptoms, and relatively rudimentary exploration of cellular biology. Also, the PR makes it sound as if the integration site is much more precise and predictable than it really is. The sites for viral integration are actually spread out between chromosome locations 19q13.3 and 19q13.4. Rearrrangements of genomic DNA are seen with wild-type virus integration. There are numerous genes in this region, and one of them is the BAX gene. Frameshift mutations in BAX occur in more than half of colon and gastric tumors with microsatellite instability (MSI), the "mutator phenotype" (MMP).

Mutational inactivation of the proapoptotic gene confers selective advantage during tumor clonal evolution. Y Ionov, H Yamamoto, S Krajewski, JC Reed, M Perucho. Proc Natl Acad Sci USA 2000 Sep 26;97(20):10872-10877. "Here we show that inactivation of the wild-type BAX allele by de novo frameshift mutations confers a strong advantage during tumor clonal evolution."

More on AAV integration:

Reference list of human DNA repair genes, update version. From "Human DNA repair genes," RD Wood, M Mitchell, J Sgouros, T Lindahl. Science 2001 Feb 16;291(5507):1284-1289.

Topics in molecular oncology: Microsatellite instability. Reviewed by Tom S Frank, University of Michigan School of Medicine, Dept. of Pathology.

The "Special Virus Cancer Program" Gang

In the 1960s and 1970s, the National Cancer Institute pretended to search for viruses in human cancer. Its highly-funded Special Virus Cancer Program was controlled by a few insiders and their cronies, who were determined to find nothing in order to scotch the idea that viruses cause human cancer.

Analysis of human tumors and malignant cell lines for BK virus-specific DNA sequences. WSM Wold, JK Mackey, KH Brackmann, N Takemori, P Rigden, M Green. Proc Natl Acad Sci 1978 Jan;75(1):454-458.

Polyoma Viruses and Polio Vaccines

cast 12-17-08