Genomic Organization of Amplified <i>MYC</i> Genes Suggests Distinct Mechanisms of Amplification in Tumorigenesis

Herrick, John H.; Conti, Chiara; Teissier, Sébastien; Thierry, Françoise; Couturier, Jérôme; Sastre-Garau, Xavier; Favre, Michel; Orth, Gérard; Bensimon, Aaron

doi:10.1158/0008-5472.can-04-2802

Cited by 38 publications

(41 citation statements)

References 45 publications

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“…The red rectangles below the X-axis localize the different amplimers used. with the pattern of the co-amplified MYC and viral sequences on DNA stretched molecules previously reported (Herrick et al, 2005), clearly indicate that, in the genital tumors analysed, integration of viral DNA occurred prior to gene amplification. In two cases, both associated with HPV18, MYC was overexpressed but not amplified.…”

Section: Discussionsupporting

confidence: 79%

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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: Discussionsupporting

confidence: 79%

“…Northern blot experiments showed that MYC was overexpressed in IC1 cells. More recently, using DNA stretching (Herrick et al, 2005), we found that MYC was co-amplified together with HPV18 DNA sequences in IC1 cells. These data suggest that MYC activation could be secondary to the insertion of HPV DNA sequences at the MYC locus.…”

Section: Introductionmentioning

confidence: 94%

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

et al. 2006

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“…2D). This fact points to an unequal sister chromatid homologue recombination as the initial amplification mechanism (30,31). It is possible that the inverted Alus found near the telomeric breakage point confer instability to this region, promoting complementary interactions in the same strand and facilitating a hairpin or a secondary structure formation leading to a unequal recombination between chromatids ( Fig.…”

Section: Discussionmentioning

confidence: 97%

Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

Morales

García

Ribas

et al. 2009

Molecular Cancer Therapeutics

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Gene amplification is one of the most frequent manifestations of genomic instability in human tumors and plays an important role in tumor progression and acquisition of drug resistance. To better understand the factors involved in acquired resistance to cytotoxic drugs via gene amplification, we have analyzed the structure and dynamics of dihydrofolate reductase (DHFR) gene amplification in HT29 cells treated with methotrexate (MTX). Analysis of the DHFR gene amplification process shows that the amplicon exhibits a complex structure that is consistently reproduced in independent treatments. The cytogenetic manifestation of the amplification in advanced stages of the treatment may be in the form of double minutes or as a homogeneously stained region. To get insights into the mechanisms of resistance, we have also investigated the sensitization to MTX of MTX-resistant cells after drug withdrawal and reexposure to MTX. Passive loss of the DHFR amplicon by withdrawal of the drug results in MTXsensitive cells exhibiting a substantial reduction of their capacity or even an incapacity to generate resistance when submitted to a second cycle of MTX treatment. On a second round of drug administration, the resistant cells generate a different amplicon structure, suggesting that the formation of the amplicon as in the first cycle of treatment is not feasible. These results indicate that DHFR gene amplification is a ''wear and tear'' process in HT29 cells and that MTX-resistant cells may become responsive to a second round of treatment if left untreated during a sufficient period of time. [Mol Cancer Ther 2009; 8(2):424 -32]

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“…They also seem to occur early, as we analyzed integration sites after only f25 population doublings in feeder-free conditions. Local rearrangement has been described in previous cell line studies (29,44,45), but it is likely to have been underreported, particularly in clinical samples, as PCR-based methods of integration site analysis would not identify it. Interestingly, it has recently been shown that latent integrants may be able to induce genomic instability in the locality of the integration site, despite no quantitative deregulation of E6 and E7, as expression of E1 and E2 proteins in cells containing integrated HR-HPV origins can induce genomic rearrangements of flanking ACAGTGCTACATTATTAAG None *The sequences were determined at the DNA level by RS-PCR, except in the case of clones Z, E3, O2, and G2 where the host-viral junction of the fusion transcript is given, as determined by APOT.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Naturally Occurring HPV16 Integration Sites Isolated from Cervical Keratinocytes under Noncompetitive Conditions

et al. 2008

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As the high-risk human papillomavirus (HPV) integrants seen in anogenital carcinomas represent the end-point of a clonal selection process, we used the W12 model to study the naturally occurring integration events that exist in HPV16-infected cervical keratinocytes before integrant selection. We performed limiting dilution cloning to identify integrants present in cells that also maintain episomes. Such integrants arise in a natural context and exist in a noncompetitive environment, as they are transcriptionally repressed by episome-derived E2. We found that integration can occur at any time during episome maintenance, providing biological support for epidemiologic observations that persistent HPV infection is a major risk factor in cervical carcinogenesis. Of 24 different integration sites isolated from a single nonclonal population of W12, 12 (50%) occurred within chromosome bands containing a common fragile site (CFS), similar to observations for selected integrants in vivo. This suggests that such regions represent relatively accessible sites for insertion of foreign DNA, rather than conferring a selective advantage when disrupted. Interestingly, however, integrants and CFSs did not accurately colocalize. We further observed that local DNA rearrangements occur frequently and rapidly after the integration event. The majority of integrants were in chromosome bands containing a cancer-associated coding gene or microRNA, indicating that integration occurs commonly in these regions, regardless of selective pressure. The cancer-associated genes were generally a considerable distance from the integration site, and there was no evidence for altered expression of nine strong candidate genes. These latter observations do not support an important role for HPV16 integration in causing insertional mutagenesis. [Cancer Res 2008;68(20):8249-59]

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Genomic Organization of Amplified MYC Genes Suggests Distinct Mechanisms of Amplification in Tumorigenesis

Cited by 38 publications

References 45 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

Dihydrofolate reductase amplification and sensitization to methotrexate of methotrexate-resistant colon cancer cells

Characterization of Naturally Occurring HPV16 Integration Sites Isolated from Cervical Keratinocytes under Noncompetitive Conditions

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