Dataset Information

Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis.

ABSTRACT: Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VIN^VSCC ) and women who did not develop VSCC during follow-up (VIN^no^VSCC ). HPV-testing resulted in 41 HPV-positive (16 VIN^VSCC , 14 VIN^no^VSCC , and 11 VSCC) and 24 HPV-negative (11 VIN^VSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VIN^VSCC had less CNA than HPV-negative VSCC (P = .009), but shared chromosome 8 alterations. HPV-positive VIN^no^VSCC had less CNA than VIN^VSCC (P = .022). Interestingly, 1pq gain was detected in 81% of HPV-positive VIN^VSCC and only in 21% of VIN^no^VSCC (P = .001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.

SUBMITTER: Swarts DRA

PROVIDER: S-EPMC6144162 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis.

Swarts Dorian R A DRA Voorham Quirinus J M QJM van Splunter Annina P AP Wilting Saskia M SM Sie Daoud D Pronk Divera D van Beurden Marc M Heideman Daniëlle A M DAM Snijders Peter J F PJF Meijer Chris J L M CJLM Steenbergen Renske D M RDM Bleeker Maaike C G MCG

Cancer medicine 20180720 9

Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by ...[more]

PMID: 30030907

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Project description:Vulvar squamous cell carcinoma (VSCC) is a biologically and morphologically diverse disease, consisting of human papillomavirus (HPV)-positive and -negative tumors that differ in their morphological phenotypes and associated vulvar mucosal disorders. This study analyzed the frequencies of allelic loss (loss of heterozygosity (LOH)) in HPV-positive and -negative VSCCs to identify potential targets for the study of preinvasive diseases, to determine whether HPV status influenced patterns of LOH, and to determine whether these patterns differed from HPV-positive tumors of another genital site, cervical squamous cell carcinomas (CSCC). DNA extracted from microdissected archival sections of two index tumors, one each HPV negative and positive, was analyzed for LOH at 65 chromosomal loci. Loci scoring positive with either sample were included in an analysis of 14 additional cases that were also typed for HPV. Frequencies of LOH at loci were computed in a panel of HPV-positive and -negative VSCCs. Twenty-nine loci demonstrated LOH on the initial screen and were used to screen the remaining 14 tumors. High frequencies of LOH were identified, some of which were similar to a prior karyotypic study (3p, 5q, 8p, 10q, 15q, 18q, and 22q) and others of which had not previously been described in VSCC (1q, 2q, 8q, 10p, 11p, 11q, 17p, and 21q). With the exception of 5q and 10p, there were no significant associations between frequency of LOH and HPV status in VSCC. LOH at 3p and 11q were frequent in both VSCC and CSCC; however, allelic losses at several sites, including 5q, 8q, 17p, 21q, and 22q, were much more common in VSCC. VSCCs exhibit a broad range of allelic losses irrespective of HPV status, with high frequencies of LOH on certain chromosomal arms. This suggests that despite their differences in pathogenesis, both HPV-positive and -negative VSCCs share similarities in type and range of genetic losses during their evolution. Whether the different frequencies of LOH observed between VSCC and CSCC are real or reflect differences in stage and/or tumor size remains to be determined by further comparisons. The role of these altered genetic loci in the genesis of preinvasive vulvar mucosal lesions merits additional study.

Project description:IntroductionApproximately 25%-43% of all vulvar carcinomas are associated with human papillomavirus (HPV). In many countries, vulvar carcinoma incidence rates are increasing, possibly due to greater HPV exposure. However, studies exploring changes in HPV prevalence and genotype distribution in vulvar carcinoma over time are scarce. Our aim was to evaluate time trends in HPV prevalence and genotype distribution in vulvar squamous cell carcinoma in an unselected, nationwide sample of Norwegian women. Further, we explored clinical and histopathological aspects in relation to HPV status and investigated whether HPV status was associated with survival.Material and methodsAll vulvar squamous cell carcinoma cases from 1970-1975 and 2000-2005 were extracted from the Cancer Registry of Norway and corresponding tissue blocks were retrieved. After detailed histology review, HPV testing was conducted using real-time TaqMan PCR. Overall survival rates were calculated using the Kaplan-Meier method. Multivariable Cox regression analysis was performed to estimate hazard ratios adjusted for age at diagnosis, stage and diagnostic period.ResultsHistological review was performed on 352 vulvar squamous cell carcinoma cases. We were able to obtain valid HPV analysis results for 282 cases, Overall, 29.8% (95% CI 24.5%-35.5%) of cases were high-risk HPV (hrHPV)-positive. When comparing the two periods, we found that the percentage of hrHPV-positive tumors increased significantly from 23% (95% CI 16.0%-31.4%) in 1970-1975 to 35.3% (95% CI 27.8%-43.3%) in 2000-2005 (P = 0.025). The predominant genotypes were HPV 16 (73%), HPV 33 (21%), and HPV 18 (6%), with similar distributions in both periods. In the more recent cohort, several additional genotypes were detected: HPV 6, 11, 39, 45, 52, 58 and 66 were found in smaller percentages, ranging from 1.8% to 3.6%. In univariate analysis, patients with HPV-positive tumors showed improved overall survival compared with patients with HPV-negative tumors (hazard ratio [HR] 0.65, 95% CI 0.48-0.86).ConclusionsThe prevalence of HPV in vulvar squamous cell carcinomas in Norway was significantly higher in 2000-2005 than in 1970-1975. The three predominant genotypes were HPV 16, 33 and 18 in both time periods. However, several other HPV genotypes have emerged over the last decades. HPV-positivity was associated with better overall survival.

Dataset Information

Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis.

Publications

Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis.

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