Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers

Ferber, Matthew J.; Montoya, Damian P.; Yu, Cecilia; Aderca, Ileana; McGee, Andrew R.; Thorland, Erik C.; Nagorney, David M.; Gostout, Bobbie S.; Burgart, Larry J.; Boix, Loreto; Bruix, Jordi; McMahon, Brian J.; Cheung, T.H.; Chung, Tony K.H.; Wong, Yick Fu; Smith, Jeremy C.; Roberts, Lewis R.

doi:10.1038/sj.onc.1206528

Cited by 211 publications

(147 citation statements)

References 32 publications

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“…Besides MYC, a number of genes, potentially involved in carcinogenesis, such as CEACAM5, FANCC (Wentzensen et al, 2002;Ferber et al, 2003b), TP63 (Wentzensen et al, 2002), TERT (Ferber et al, 2003a), MYOF, Ribosomal protein gene RPS27 (Klimov et al, 2002), MYCN (Sastre-Garau et al, 2000), NFIB (Ziegert et al, 2003), have also been found to correspond to targets for the insertion of HPV DNA. In spite of this diversity, only a few cases with an integration pattern compatible with a mechanism of insertional mutagenesis have been observed (Wentzensen et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

et al. 2006

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To determine whether integration of human papillomavirus (HPV) DNA sequences could lead to the deregulation of genes implied in oncogenesis, we analysed the HPV integration sites in a series of nine cell lines derived from invasive genital carcinomas. Using in situ hybridization, HPV16 or 18 sequences were found at chromosome band 8q24, the localization of MYC, in IC1, IC2, IC3, IC6 and CAC-1 cells and at other sites in IC4, IC5, IC7 and IC8 cells. We then localized viral sequences at the molecular level and searched for alterations of MYC structure and expression in these cells. MYC genomic status and viral integration sites were also analysed in primary tumors from which IC1, IC2, IC3 and IC6 cells were derived. In IC1, IC2 and CAC-1 cells, HPV DNA was located within 58 kb of MYC, downstream, upstream, or within MYC. In IC3 and IC6 cells, HPV DNA was located 400-500 kb upstream of MYC. Amplification studies showed that, in IC1, IC2 and IC3, viral and MYC sequences were coamplified in an amplicon between less than 50 and 800 kb in size. MYC amplification was also observed in primary tumors, indicating that this genetic alteration, together with viral insertion at the MYC locus, had already taken place in vivo. MYC was not amplified in the other cell lines. MYC mRNA and protein overexpression was observed in the five cell lines in which the HPV DNA was inserted close to the MYC locus, but in none of the lines where the insertion had occurred at other sites. MYC activation, triggered by the insertion of HPV DNA sequences, can be an important genetic event in cervical oncogenesis.

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Section: Discussionmentioning

confidence: 99%

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

et al. 2006

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“…With this approach, we have demonstrated that (1) HBV insertion into cellular genes is in fact frequent (around 70%) and (2) HBV integration can occur in genes encoding for proteins with a fundamental role in the control of cell signaling, proliferation and viability (Figure 2) (Horikawa and Barrett, 2001;Ferber et al, 2003;Paterlini-Brechot et al, 2003;Murakami et al, 2005;Tamori et al, 2005). Most importantly, our work, combined with recent investigations from other groups, has also led to demonstrate that the telomerase and mixed lineage leukemia encoding genes are in fact targeted by HBV in different HBV-related HCCs, thus suggesting common pathways in HBV-related carcinogenesis (Horikawa and Barrett, 2001;Ferber et al, 2003;Paterlini-Brechot et al, 2003;Murakami et al, 2005;Tamori et al, 2005). Figure 2 The insertion of HBV genome in cellular genes frequently targets genes that regulate key cellular pathways.…”

Section: Hbv-related Hcc D Kremsdorf Et Almentioning

confidence: 99%

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

et al. 2006

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As discussed in detail in other chapters of this review, chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated with the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarize the current knowledge on the mechanisms involved in HBVrelated liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus, as well as between viral infections and other environmental factors, such as alcohol.

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“…Second, insertional mutations have been described in which HBV integration at specific sites activates endogenous genes such as retinoic acid b-receptor (Dejean et al, 1986), cyclin A (Wang et al, 1990) and mevalonate kinase (Graef et al, 1994). More recently, 15 new genes were found to be altered by an HBV integration in tumors, suggesting that viral integration in the vicinity of genes controlling cell proliferation, viability and differentiation is a mechanism frequently involved in HBV hepatocarcinogenesis (Ferber et al, 2003;Horikawa and Barrett, 2003;Paterlini-Brechot et al, 2003). All of these integration events are unique, except for the human telomerase reverse transcriptase (hTERT) and the inositol 1,4,5-triphosphate receptor (IPR) genes that have been observed to have site-specific HBV integrations in independent tumors (Ferber et al, 2003;Horikawa and Barrett, 2003;Paterlini-Brechot et al, 2003).…”

Section: Genetic Alterations and Hepatitis B Virus Infectionmentioning

confidence: 99%

Genetics of hepatocellular tumors

2006

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Numerous genetic alterations are accumulated during the process of hepatocarcinogenesis. These genetic alterations can be divided into two groups. The first set of genetic alterations is specific of hepatocellular tumor risk factors. It includes integration of hepatitis B virus (HBV) DNA, R249S TP53 (tumor protein p53) mutation in aflatoxin B1-exposed patients, KRAS mutations related to vinyl chloride exposure, hepatocyte nuclear factor 1a (HNF1a) mutations associated to hepatocellular adenomas and adenomatosis polyposis coli (APC) germline mutations predisposing to hepatoblastomas. The second set of genetic alterations are etiological nonspecific, it includes recurrent gains and losses of chromosomes, alteration of TP53 gene, activation of WNT/b-catenin pathway through CTNNB1/b-catenin and AXIN (axis inhibition protein) mutations, inactivation of retinoblastoma and IGF2R (insulin-like growth factor 2 receptor) pathways through inactivation of RB1 (retinoblastoma 1), P16 and IGF2R. Comprehensive analyses of these genetic alterations have defined two pathways of hepatocarcinogenesis according to the presence or the absence of chromosomal instability. Hepatitis B virus and poorly differentiated tumors are related to chromosome instable tumors associated with frequent TP53 mutations, whereas non-HBV and well-differentiated tumors are related to chromosomal stable samples that are frequently b-catenin activated. These classifications have clinical relevance as genetic alterations may also be related to prognosis.

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Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers

Cited by 211 publications

References 32 publications

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

Genetics of hepatocellular tumors

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