Common fragile sites are preferential targets for HPV16 integrations in cervical tumors

Thorland, Erik C.; Myers, Shannon L.; Gostout, Bobbie S.; Smith, Jeremy C.

doi:10.1038/sj.onc.1206170

Cited by 229 publications

(225 citation statements)

References 59 publications

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“…Extensive analyses of retrovirus integration sites have shown that active genes (Schroder et al, 2002) or transcription start regions (Wu et al, 2003) are preferential integration targets. Fragile sites have also been reported to facilitate HPV DNA integration (Thorland et al, 2003), but other factors may influence the nature of the genetic rearrangements that implicate insertion of foreign DNA and illegitimate recombination. In Burkitt lymphoma, the frequency of the different types of translocation observed was highly correlated with the probability that the two partners were in physical proximity in the cell nucleus (Roix et al, 2003).…”

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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“…This mechanism could be related to the stimulation of host cell cycle, inhibition of cellular apoptosis, cell growth, and escape from the host immune system, leading to cellular proliferation in multistep tumorigenesis. It has also been reported that HPV integration occurs in chromosomal fragile sites (Thorland et al, 2003). Common fragile sites are thought to be highly unstable and preferential sites for translocations, deletions, intrachromosomal gene amplification, and integration of plasmid DNA and tumor viruses, such as SV40 (Smith et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

et al. 2005

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Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P ¼ 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.

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“…Studies in cell cultures have shown that under replication stress conditions fragile sites are hotspots for sister chromatid exchange, translocations and deletions (Glover and Stein, 1987;Glover and Stein, 1988;Wang et al, 1997). In vivo, fragile sites correlate with chromosomal breakpoints in tumors (Hecht and Hecht, 1984;Yunis and Soreng, 1984) and with integration sites of oncogenic viruses (Thorland et al, 2003;Bester et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Interplay between ATM and ATR in the regulation of common fragile site stability

et al. 2007

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Common fragile sites are specific genomic loci that form constrictions and gaps on metaphase chromosomes under conditions that slow, but do not arrest, DNA replication. These sites have been shown to have a role in various chromosomal rearrangements in tumors. Different DNA damage response proteins were shown to regulate fragile site stability, including ataxia-telangiectasia and Rad3-related (ATR) and its effector Chk1. Here, we investigated the role of ataxia-telangiectasia mutated (ATM), the main transducer of DNA double-strand break (DSB) signal, in this regulation. We demonstrate that replication stress conditions, which induce fragile site expression, lead to DNA fragmentation and recruitment of phosphorylated ATM to nuclear foci at DSBs. We further show that ATM plays a role in maintaining fragile site stability, which is revealed only in the absence of ATR. However, the activation of ATM under these replication stress conditions is ATR independent. Following conditions that induce fragile site expression both ATR and ATM phosphorylate Chk1, suggesting that both proteins regulate fragile site expression probably via their effect on Chk1 activation. Our findings provide new insights into the interplay between ATR and ATM pathways in response to partial replication inhibition and in the regulation of fragile site stability.

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Common fragile sites are preferential targets for HPV16 integrations in cervical tumors

Cited by 229 publications

References 59 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 insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

Interplay between ATM and ATR in the regulation of common fragile site stability

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