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

Peter, Martine; Rosty, Christophe; Couturier, Jérôme; Radvanyi, François; Teshima, Hideo; Sastre-Garau, Xavier

doi:10.1038/sj.onc.1209625

Cited by 119 publications

(128 citation statements)

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“…For instance, it has been shown that MYC activation secondary to the insertion of HPV16 or 18 genome at the MYC locus was preferentially associated with adenocarcinoma. 42 It is thus possible that secondary genetic alterations play a role in the differentiation of tumour cells.…”

Section: Discussionmentioning

confidence: 99%

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Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Crémoux

Rochefordière

Savignoni

et al. 2008

Intl Journal of Cancer

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Human papillomavirus (HPV) DNA sequences are associated with the large majority of invasive cervical carcinoma but the role of specific genotype(s) in the outcome of the disease is still debated. To determine the viral epidemiology in the French population of patients and the prognostic value of HPV genotypes in cervical cancer, we performed a retrospective study in 515 patients treated in our Institution from 1985 to 2005. Ninety-six percent of the cases were found associated with HPV DNA whereas 4% remained HPV negative. High-risk HPV 16/18 genotypes were found in 70% of the cases. HPV 18 was more frequently associated with adenocarcinoma (40.6%) than HPV 16 (10.4%) and found in tumours developed in younger women (mean age, 45.8 years) than HPV 16 (48.3 years) or other HPV types (53.6 years). In multivariate analysis, node involvement (p < 0.0001), parametria invasion (p 5 0.009), tumour size (p 5 0.01) and HPV status (p 5 0.02) were associated with disease-free survival (median follow-up 95 months). Disease outcome was better in tumours associated with intermediate risk HPV types (HPV 31,33,35,39, 52, 53, 58, 59, 73) than in tumours with high oncogenic types (HPV 16, 18, 45) (p 5 0.03). Node status and tumour size remained prognostic factor for overall survival. Our data show that HPV genotype is one of the biological factors associated with the outcome of cervical cancer. One third of invasive carcinoma were not associated with HPV 16/18, indicating that the screening for cervical neoplasia should be maintained after prophylactic vaccination against these HPV genotypes. ' 2008 Wiley-Liss, Inc.Key words: cervical cancer; HPV; prognosis Human papillomavirus (HPV) DNA sequences are associated with most of invasive cervical carcinoma worldwide 1 and the role of HPV as a causative agent of cervical neoplasia is well documented. 2 There is a large plurality of HPV types since more than 100 different genotypes have been identified 3 among which more than 40 infect ano-genital mucosa. Histological and virological analyses have shown that 3 groups of genital HPV could be identified according to their oncogenic properties. Low-risk HPVs (HPV6,11,42,43, 44. . .), present in low grade cervical intraepithelial neoplasia (CIN) but rare in invasive cancer, intermediaterisk HPVs (HPV 31,33,35, 51, 52, 58. . .), more prevalent in CIN than in invasive cancer, and high-risk HPVs (HPV16, 18, 45, 56. . .), more frequently found in invasive carcinoma than in CIN. 4 Experimental data have disclosed that high-risk E6 and E7 oncoprotein act in the tumour process by interfering with cell cycle G1-S checkpoint. 5 Virological epidemiology data show that HPV16 and HPV18 are the most prevalent genotypes found in invasive carcinoma worldwide but that there are significant geographic variations in the prevalence of less common genotypes. 6 In the perspective of prophylactic vaccination, it is thus necessary to accurately determine the prevalence of the different HPV types in cervical cancer at country level. Moreover, controversial data...

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Section: Discussionmentioning

confidence: 99%

“…Histological and virological analyses have shown that 3 groups of genital HPV could be identified according to their oncogenic properties. Low-risk HPVs (HPV6, 11,42,43,44. .…”

mentioning

confidence: 99%

Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Crémoux

Rochefordière

Savignoni

et al. 2008

Intl Journal of Cancer

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“…The 8q24 region has also been shown to be a frequent site of HPV integration and is often amplified in cervical cell lines and cervical lesions. [25][26][27][28][29] MYC genes are key regulators of cell proliferation, and enhanced expression of MYC genes promotes unrestricted proliferation and contributes to the genesis of most human tumors. 30 The 3q26 chromosome region was proposed as an important marker for disease progression in several studies.…”

Section: Discussionmentioning

confidence: 99%

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

Соколова

Algeciras‐Schimnich

Song

et al. 2007

The Journal of Molecular Diagnostics

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The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. In the last decade, the etiological role of human papillomavirus (HPV) infection in the development of cervical dysplasia and cancer has been well established.1-4 The frequency of HPV infection in women with a diagnosis of atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), or high-grade squamous intraepithelial lesion (HSIL) is approximately 50, 80, and 95%, respectively. 5-7Still, only a fraction of HPV-infected women will develop high-grade lesions and cervical cancer. 8HPV infections compromise normal cellular proliferation through degradation of the tumor suppressor proteins p53 and pRB by viral proteins E6 and E7, respectively. In addition, HPV infection has been shown to induce abnormal centrosome duplication early in the infection process.9 -12 HPV infection of replicating immature cells prevents epithelial maturation and differentiation, leading to continued replication and accumulation of genetic abnormalities. 2,13,14 Chromosomal instability at a numerical or structural level is a hallmark of malignant tumors.9 Deletion, duplication, and amplification of various genomic regions have been demonstrated in cervical cancer by comparative genomic hybridization and fluorescence in situ hybridization (FISH) methods. [15][16][17][18] In an internal study, we assessed biopsy specimens showing high-grade dysplasia and cancer with FISH probes to 35 unique loci and identified 2 loci, the 3q26 region (comprising H-TERC gene) and the 8q24 region (comprising c-MYC gene), which showed highest frequency of copy number gains in high-grade dysplasia and cancer. Because these loci are frequently altered in cervical cancer tumorigenesis, 16,17,19,20 we hypothesized that they might be useful markers for the detection of cervical dysplasia and carcinoma.To explore this further, we created a fluorescence in situ hybridization assay that allows for the simultaneous Supported by a grant from Abbott Molecular (to K.C.H.).

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“…The physical state of the virus and its interaction with the host genome in HPV-associated tumors has been well-characterized in cervical cancer (24)(25)(26)(27)(28)(29)(30), but less is known about the molecular architecture of HPV infection in HNC (31,32). Recently, a comprehensive genome-wide analysis of HPV integration in human cancers showed associations between HPV integrants and extensive host genomic amplifications and rearrangements, including deletions, inversions, and chromosomal translocations (12).…”

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confidence: 99%

Characterization of HPV and host genome interactions in primary head and neck cancers

Parfenov¹,

Pedamallu²,

Gehlenborg³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

338

474

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Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twentyfive cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter-and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.cancer | head and neck | papilloma virus | genome rearrangement | integration sites H ead and neck cancer (HNC) is a heterogeneous group of tumors characterized by a common anatomic origin, and most such tumors develop from within the mucosa and are classified as head and neck squamous cell carcinomas (HNSCCs) (1). HNSCC, the sixth most common cancer diagnosed worldwide and the eighth most common cause of cancer death (2), is frequently associated with human papillomavirus (HPV) infection (3, 4). Depending on the anatomic site of the tumor, HPV prevalence is estimated at 23-36% (5). HPV-positive HNSCCs form a distinct subset of HNCs that differs from HPV-negative HNSCCs in tumor biology and clinical characteristics, including superior clinical outcomes (6-9).The molecular pathogenesis of HPV-driven HNSCC also seems distinct from HPV-negative tumors, with previous studies showing a divergent spectrum of alterations in gene expression, mutations, amplifications, and deletions as well as distinct epigenome alterations (10-15). HPV is known to drive tumorigenesis through the actions of its major oncoproteins E6 and E7, which target numerous cellular pathways, including inactivation of p53 and the retinoblastoma (Rb) protein (16-18). Together with E5, they also play an important role in immune evasion, being involved in both innate and adaptive immunity (19,20).Initially after infection, HPV is identified in circular extrachromosomal particles or episomes. A critical step in progression to cancer is the integration of viral DNA into the host cell Significance A significant proportion of head and neck cancer is driven by human papil...

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

Cited by 119 publications

References 59 publications

Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Different outcome of invasive cervical cancer associated with high‐risk versus intermediate‐risk HPV genotype

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

Characterization of HPV and host genome interactions in primary head and neck cancers

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