the association between chronic viral infection and human malignancy is well established : papillomaviruses are involved in the pathogenesis of human cervical cancer ( dell and gaston 2001 ) , epstein - barr virus has been linked to burkitt 's lymphoma , nasopharyngeal carcinoma , post - transplant lymphoma , hodgkin 's disease , and gastric carcinoma ( thompson and kurzrock 2004 ) ; hepatitis viruses b and c are associated with hepatocellular carcinoma ( monto and wright 2001 ) , simian virus 40 has been linked to mesothelioma ( rizzo et al . the mechanisms responsible for the malignant transformation in cases of long - lasting viral infection differ according to the particular virus and cancer and have been extensively studied . an established association between viral infection and cancer may lead the way for development of a vaccine which could prevent both the infection as well as the malignant transformation . incorporation of viral dna may interfere with the normal sequence of human dna bases , in a genetic manner , or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation . activation of oncogenes or silencing of tumor suppressor genes may be the result of long lasting inflammation . these gene products enhance proliferation and inhibit apoptosis and differentiation , driving the cells towards carcinogenesis . chromosomal instability has been established as the key mechanistic component of cancer development ( fearon and vogelstein 1990 ) . later , it was found that crc results not only from the progressive accumulation of genetic alteration , but also from epigenetic changes ( lengauer et al . three main pathways have been described : chromosomal instability ( cin ) , microsatellite instability ( msi ) , and cpg island methylation phenotype ( cimp ; boland and goel 2010 ) . microsatellite instability is involved in the genesis of about 15% of crcs ( ionov et al . 1993 ; thibodeau et al . the multiple errors in repetitive dna sequences ( microsatellites ) result from a failure of the dna mismatch repair system to edit errors made during dna replication ( carethers and boland 2003 ) . this system is inactivated either by hypermethylation of the promoter , which silences gene transcription of hmlh1 ( epigenetic phenomenon in sporadic crc ) , or because of germ - line mutations ( herman et al . other genes of the mismatch repair family , such as msh2 , msh6 , and pms2 may be inactivated by genetic processes , and cause lynch syndrome . dna methylation is mediated by dna methyltransferase catalyzing the transfer of a methyl group from methyl donor s - adenosil - methyonine to 5 cytosine postponed by guanine and forming methylcytosine ( lyko et al . the overall frequency of cpg dinucleotides is relatively low in the human genome and accounts for approximately 1% of total dna bases ( ehrlich et al . . however , up to 60% of genes have a 5 promoter region with 0.32  kb stretches of dna called  cpg island  ( bird 1986 ) . the great majority of cpg dinucleotides which are not associated with cpg islands are heavily methylated ; however , cpg dinucleotides in cpg islands of promoter regions are usually unmethylated , whether or not the gene is being transcribed ( antequera and bird 1993 ) . cancer gene genomes simultaneously show global hypomethylation , specific promoter hypermethylation of tumor suppressor genes , and hypomethylation of oncogenes ( gaudet et al . in addition to dna methylation , common epigenetic changes in cancer include histone modification by acethylation ( jenuwein and allis 2001 ) . some of transcription factors can not bind to dna with methylated cpg island to start transcription ( prendergast and ziff 1991 ) . additionally , methylated dna has general effect on chromatin . mbps are part of complexes containing histone deacetylases that inactivate chromatin configuration around gene and silenced gene expression by exclusion of transcriptional factors ( nan et al . tumors with high - frequency microsatellite instability tend to be diploid to possess a mucinous histology and to have a surrounding lymphoid reaction . they are more prevalent in the proximal colon , have a rapid ( 23  years ) progression from adenomatous polyp to cancer , and are insensitive to 5-fluoro - uracil - based chemotherapy . nevertheless , they are associated with longer survival than stage - matched tumors with microsatellite stability ( lothe et al . 1993 ; gryfe et al . 2000 ; halling et al . 1999 ; thibodeau et al . deng and colleagues demonstrated that , in crc , regional hypermethylation and global hypomethylation are associated with altered chromatin conformation and histone acetylation , which have a causal correlation with msi and cin , respectively ( deng et al . msi cancers had closed chromatin conformation and low levels of histone acetylation . gene silencing is mediated by genetic processes , such as mutation , deletion , or insertion of nucleotides or by epigenetic mechanisms such as methylation of the cpg island in a gene promoter by the enzyme dna methyltransferase . this group of substances may decrease or increase proliferation by silencing oncogenes or tumor suppressor genes . whether cpg island hypermethylation constitutes a mechanism for mirna silencing , and balaguer and colleagues demonstrated that epigenetic silencing of mir-137 is an early event in colorectal carcinogenesis ( balaguer et al . some oncoviruses , including jc virus , may initiate carcinogenesis by epigenetic modification of different oncogenes . jc virus , a small non - enveloped negatively supercoiled 5,130  bp dsdna virus , is a member of the polyomavirus family , which includes bk virus , sv40 , and , recently described , ki virus , wu virus , and mc virus ( white and khalili 2004 ; allander et al . jcv was first isolated in 1971 from the brain of a patient ( john cunningham ) with hodgkin 's lymphoma who developed progressive multifocal encephalopathy after chemotherapy . structurally , jcv contains only six genes which encode the t- and t - antigens , three viral capsid proteins ( vp1 - 3 ) , and an agnoprotein involved in viral assembly . the t - ag takes up over half of the viral genome ( raj et al . possess neutralizing antibodies to the virus , some 50% of adults shed jcv dna in the urine ( kitamura et al . 1994 ; rossi et al . 1996 ; sabath and major 2002 ) ; however , the viral genome has also been detected in tissue samples from brain , lung , spleen , liver , tonsils , and stomach to colon . it may act by stabilizing -catenin , facilitating its entrance to the cell nucleus and starting proliferation and cancer formation . diploid crc cell lines transfected with jcv - containing plasmids developed cin ( niv et al . this result provided direct experimental evidence for the ability of t - ag to induce cin in the genome of colonic epithelial cells . the association of hmlh1 promoter methylation and tumor positivity for jc virus in crc was recently documented ( goel et al . jc virus t - ag dna sequences found in 77% of crcs were associated with promoter methylation of multiple genes ( fig .  1 ) . hmlh1 was methylated in 25 out of 80 crc patients positive for t - ag ( 31% ) in comparison with only one out of 11 negative cases ( 9% ) . this observation is somewhat unexpected since , in this case , suppression of dna repair by silencing hmlh1 gene should be sufficient to cause genomic instability and uncontrolled proliferation . we confirmed this observation in a small sample of israeli patients ( niv et al . , we looked at both jcv t - ag in the crc tissue and hmlh1 promoter methylation in different ethnic groups in israel with different incidences of crc . we found 83.3% positivity of the tumors for jcv t - ag , which is very similar to that in previous publications ( laghi et al . unexpectedly , we demonstrated hmlh1 promoter methylation only in jcv t - ag - positive tumors . 1working hypothesis : jc virus t - ag initiates proliferation through wnt signaling or hypermethylation of hmlh1 working hypothesis : jc virus t - ag initiates proliferation through wnt signaling or hypermethylation of hmlh1 nosho et al . ( 2009 ) , in large study that included 766 patients with sporadic colorectal cancer , investigated the correlation between expression of t - ag in tumor tissue and different molecular alterations ( msi , cimp , cin , loss of heterozygosity of different loci , braf and kras mutation , p53 , b - catenin , cyclin d1 , and cyclooxygenase-2 expression ) . in this study , jcv t - ag was demonstrated in 35% of tumors , but , in contrast to results of goel and colleagues , expression of t - ag was inversely associated with msi and cimp . in multivariate logistic regression analysis , jcv t - ag expression was independently associated with p53 expression and cin . ( 2008 ) investigated the association between jcv t - ag expression and methylator phenotype in 50 cases of colorectal adenoma . t - ag expression was demonstrated in 16 ( 32% ) of cases , and the proportion of positive cases increased progressively from unmethylated cases to cimp - low and cimp - high . an association between methylation and exposure to carcinogens such as viruses has been observed before but has not led to mechanistic insights into the process ( boland et al . 2005 ; shen et al . human papillomavirus chronic infection is associated with methylation of several genes involved in carcinogenesis such as apc , cdkn2a , pten , and others ( whiteside et al . similarly , in nasopharyngeal carcinoma associated with epstein - barr virus ( ebv ) , hypermethylation of certain cellular promoters is attributed to the up - regulation of dna methyltransferase1 ( dnmt1 ) by the viral oncoprotein lmp1 via jnk / ap1-signaling ( niller and wolf 2009 ) . the primary molecular abnormality in ebv - associated gastric cancer is global cpg island methylation in the promoter region of many cancer - related genes ( fukayama 2010 ) . viral latent membrane protein 2a up - regulates cellular dnmt1 through phosphorylation of stat3 and hypermethylation and silencing of the tumor suppressor gene , pten . increased dnmt1 also caused methylation of e - cadherin , hmlh1 , and thbs-1 genes , and . demonstrated significant alteration in dna methylation patterns that affected the transcription of cellular genes ( doerfler 2009 ) . foreign dna may cause extensive methylation in cellular genome segments even at loci remote from the site of insertion . in addition , down - regulation of microrna by viral component can induce aberrant dna methylation by targeting dna methyltransferase 1 , as demonstrated in hepatitis b virus - related hepatocellular carcinoma , in this case , mir-152 ( huang et al . jc virus can mediate both cin and aberrant methylation in crc . like other viruses , chronic infection with jcv gene promoter methylation induced by jcv may be an important process in crc and the polyp - carcinoma sequence . further research in this field is needed , looking at a possible association between hnpcc tumors and jcv , the presence of jcv in normal mucosa of cancer - free patients , association between jcv with prognosis , and survival in crc cases of cin , cimp , and msi pathways .