Dataset Information

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature.

ABSTRACT:

Background

The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs.

Methods

We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined.

Results

We identified a total of 3459 mutations with an average of 10 mutations per megabase and a median of 28 variants per sample. The most frequently mutated genes were KALRN (28%), SPTBN1 (32%), KMT2A (31%), ZNRF3 (9%), BNC2 (12%), NOTCH2 (25%), FGFR2 (12%), SMAD2 (6%), and AR (13%). Our findings were dominated by COSMIC signature 5 and 12, represented in other head and neck cancers and in hepatocellular carcinomas, respectively.

Conclusions

We have identified multiple genetic aberrations in HPV+ OPSCCs, and the COSMIC signature 12 as most prevalent. The mutations harbour both therapeutic and prognostic potential.

SUBMITTER: Gronhoj C

PROVIDER: S-EPMC5992702 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature.

Grønhøj Christian C Jensen David H DH Agander Tina T Kiss Katalin K Høgdall Estrid E Specht Lena L Bagger Frederik Otzen FO Nielsen Finn Cilius FC von Buchwald Christian C

BMC cancer 20180607 1

<h4>Background</h4>The genetic profile for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinomas (OPSCC) remains largely unknown. The purpose of this study was to sequence tissue material from a large cohort of locoregionally-advanced HPV+ OPSCCs.<h4>Methods</h4>We performed targeted deep sequencing of 395 cancer-associated genes in 114 matched tumor/normal loco-regionally advanced HPV+ OPSCCs. Mutations and copy number aberrations were determined.<h4>Results</h4>We identi ...[more]

PMID: 29879932

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Project description:Importance:Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. Objective:To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16-positive/p16-positive OPSCCs. Design, Setting, and Participants:This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16-positive OPSCC. A total of 21 HPV 16/p16-positive tumors were used in this study. Main Outcomes and Measures:Gene expression profiles of node-negative vs node-positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Results:Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node-positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative-like from node-positive-like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population's prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63-1.00). Conclusions and Relevance:Many HPV-16 and p16-positive tumors are treated as "lower-risk," but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker.

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.

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.

Dataset Information

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature.

Background

Methods

Results

Conclusions

Publications

Deep sequencing of human papillomavirus positive loco-regionally advanced oropharyngeal squamous cell carcinomas reveals novel mutational signature.

Similar Datasets

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