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Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas.

ABSTRACT: The role of human papillomavirus (HPV) in anal squamous cell carcinoma (ASCC) carcinogenesis has been clearly established, involving the expression of viral oncoproteins and optional viral DNA integration into the host genome. In this article, we describe the various mechanisms and sites of HPV DNA insertion and assess their prognostic and predictive value in a large series of patients with HPV-positive ASCC with long-term follow-up. We retrospectively analyzed 96 tumor samples from 93 HPV-positive ASCC patients using the Capture-HPV method followed by Next-Generation Sequencing, allowing determination of HPV genotype and identification of the mechanisms and sites of viral genome integration. We identified five different mechanistic signatures of HPV insertions. The distribution of HPV signatures differed from that previously described in HPV-positive cervical carcinoma (p < 0.001). In ASCC samples, the HPV genome more frequently remained in episomal form (45.2%). The most common signature of HPV insertion was MJ-SC (26.9%), i.e., HPV-chromosomal junctions scattered at different loci. Functionally, HPV integration signatures were not associated with survival or response to treatment, but were associated with viral load (p = 0.022) and PIK3CA mutation (p = 0.0069). High viral load was associated with longer survival in both univariate (p = 0.044) and multivariate (p = 0.011) analyses. Finally, HPV integration occurred on most human chromosomes, but intragenic integration into the NFIX gene was recurrently observed (n = 4/51 tumors). Overall, the distribution of mechanistic signatures of HPV insertions in ASCC was different from that observed in cervical carcinoma and was associated with viral load and PIK3CA mutation. We confirmed recurrent targeting of NFIX by HPV integration, suggesting a role for this gene in ASCC carcinogenesis.

SUBMITTER: Morel A

PROVIDER: S-EPMC6966520 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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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:Background and purposeHuman papillomavirus-associated oropharyngeal squamous cell carcinoma is increasing in prevalence and typically occurs in younger patients than human papillomavirus-negative squamous cell carcinoma. While imaging features of human papillomavirus-positive versus human papillomavirus-negative squamous cell carcinoma nodal metastases have been described, characteristics distinguishing human papillomavirus-positive from human papillomavirus-negative primary squamous cell carcinomas have not been well established. The purpose of this project was to evaluate the use of texture features to distinguish human papillomavirus-positive and human papillomavirus-negative primary oropharyngeal squamous cell carcinoma.Materials and methodsFollowing institutional review board approval, 40 patients with primary oropharyngeal squamous cell carcinoma and known human papillomavirus status who underwent contrast-enhanced CT between December 2009 and October 2013 were included in this study. Segmentation of the primary lesion was manually performed with a semiautomated graphical-user interface. Following segmentation, an in-house-developed texture analysis program extracted 42 texture features from each segmented volume. A t test was used to evaluate differences in texture parameters between human papillomavirus-positive and human papillomavirus-negative squamous cell carcinomas.ResultsOf the 40 included patients, 29 had human papillomavirus-positive oropharyngeal squamous cell carcinoma and 11 had human papillomavirus-negative oropharyngeal squamous cell carcinoma. Significant differences were seen in the histogram parameters median (P = .006) and entropy (P = .016) and squamous cell carcinoma entropy (P = .043).ConclusionsThere are statistically significant differences in some texture features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal tumors. Texture analysis may be considered an adjunct to the evaluation of human papillomavirus status and characterization of squamous cell carcinoma.

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Mechanistic Signatures of Human Papillomavirus Insertions in Anal Squamous Cell Carcinomas.

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