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Genomic landscape of oral cancers (Illumina RNA-Seq)

ABSTRACT: Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

PROVIDER: EGAS00001003237 | EGA |

REPOSITORIES: EGA

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Genomic landscape of oral cancers (Complete Genomics WGS)

Project description:Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCC) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCC, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. By contrast, in HPV-negative OSCC, T>C substitutions in the sequence context 5’-ATN-3’ correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCC. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA, KMT2D, FGFR3, FBXW7, DDX3X, PTEN, TRAF3, RB1, CYLD, RIPK4, ZNF750, EP300, CASZ1, TAF5, RBL1, IFNGR1 and NFKBIA. Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon and nuclear factor-B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr. 11q (including CCND1) and 14q (including DICER1 and AKT1) were recurrently lost in HPV-positive OSCC, in contrast to their gains in HPV-negative OSCC. High-ranking variant allele fractions implicated ZNF750, PIK3CA and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts.

| EGAS00001002393 | EGA

Genomic landscape of oral cancers (Illumina WGS)

| EGAS00001003228 | EGA

Comparative gene expression profiling of tobacco-associated HPV-positive versus negative oral squamous carcinoma cell lines

Project description:HPV-positive oral squamous cell carcinomas (OSCCs) are specific biological and clinical entities, characterized by a more favorable prognosis compared to HPV-negative OSCCs and occurring generally in non-smoking and non-drinking younger individuals. However, poor information is available on the molecular and the clinical behavior of HPV-positive oral cancers occurring in smoking/drinking subjects. Thus, this study was designed to compare, at molecular level, two OSCC cell lines, both derived from drinking and smoking individuals and differing for presence/absence of HPV infection.

2019-12-01 | E-MTAB-6152 | biostudies-arrayexpress

Genome wide DNA methylation in oral squamous cell carcinoma (OSCC) disease and adjacent normal tissue samples

Project description:Genome wide DNA methylation profiling of normal and adjacent OSCC samples. The Illumina Infinium 450k Human DNA methylation Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 4,50,000 CpGs in tissue samples. Total 21 samples were taken including 10 paired and 1 unpaired tissues. 6 were HPV Positive and 5 were HPV negative.

2017-03-09 | GSE87053 | GEO

Gene expression analysis of head and neck squamous cell carcinoma (HNSCC) cell lines.

Project description:Human cancer cell lines are the most frequently used preclinical models in the study of cancer biology and the development of therapeutics. Although anatomically diverse, human papillomavirus (HPV)-driven cancers have a common etiology and similar mutations that overlap with but are distinct from those found in HPV-negative cancers. Building on prior studies that have characterized subsets of head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESC) cell lines separately, we performed genomic, viral gene expression, and viral integration analyses on 74 cell lines that include all readily-available HPV-positive (9 HNSCC, 8 CESC) and CESC (8 HPV-positive, 2 HPV-negative) cell lines and 55 HPV-negative HNSCC cell lines. We used over 700 human tumors for comparison. Mutation patterns in the cell lines were similar to those of human tumors. We confirmed HPV viral protein and mRNA expression in the HPV-positive cell lines. We found HPV types in three CESC cell lines that are distinct from those previously reported. We found that cell lines and tumors had similar patterns of viral gene expression; there were few sites of recurrent HPV integration. As seen in tumors, HPV integration did appear to alter host gene expression in cell lines. The HPV-positive cell lines had higher levels of p16 and lower levels of Rb protein expression than did the HPV-negative lines. Although the number of HPV-positive cell lines is limited, our results suggest that these cell lines represent suitable models for studying HNSCC and CESC, both of which are common and lethal.

2018-11-15 | GSE122512 | GEO

New Insights into the impact of Human Papillomavirus on Oral Cancer in Young Patients: Proteomic Approach Reveals a Novel Role for S100A8

Project description:Human Papillomavirus (HPV) infection has been recently linked to a subset of cancers affecting the oral cavity. However, the molecular mechanisms underlying HPV-driven oral squamous cell carcinoma (OSCC) onset and/ progression are poorly understood. Methods: We perform a MS-based proteomic profiling based on HPV status on OSCC in young patients, following biological characterization and cell assays to explore the proteome functional landscape. Results: Thirty-nine proteins are differentially abundant between HPV (+) and HPV (-) OSCC. Among them, COPS3, DYHC1, and S100A8 are unfavorable for tumor recurrence and survival in contrast to A2M and Serpine1, which low levels show association with better DFS. Remarkably, S100A8 is considered an independent prognostic factor for lower survival rate, and at high levels, it alters tumor-associated immune profiling, showing a lower proportion of M1 macrophages and dendritic cells. HPV (+) OSCC also displayed the pathogen-associated patterns receptor which, when activated, triggered S100A8 and NFκB inflammatory responses. Conclusion: HPV (+) OSCC has a peculiar microenvironment pattern, distinctively of HPV (-), involving expression of pathogen-associated pattern receptors, S100A8 overexpression, and NFκB activation and responses that had important consequences in prognosis and may guide therapeutic decisions.

2023-07-20 | PXD041856 | Pride

Genome-wide LOH and DNA copy number alteration in HPV-neg OSCC and their associations with disease-specific survival

Project description:Oral squamous cell carcinoma (OSCC) is associated with high case-fatality. To gain insight into the complexity of OSCC and to identify potential chromosomal changes that may be associated with OSCC mortality, we examined paired DNA from peripheral blood and tumor cells to assess genome-wide LOH and DNA copy number alteration (CNA) and their associations with risk factors, tumor characteristics, and disease-specific mortality among 75 patients with HPV-negative OSCC. We found a highly heterogeneous and complex genomic landscape of HPV-negative tumors, and identified regions in 4q, 8p, 9p, and 11q that seem to play an important role in oral cancer biology and survival from this disease. We used Affymetrix 6.0 SNP arrays to test paired DNA from peripheral blood and tumor cells isolated by laser capture microdissection from 75 patients with HPV-negative OSCC. Peripheral blood DNA is used as reference for CNA to LOH.

2016-03-23 | E-GEOD-68717 | biostudies-arrayexpress

mRNA sequencing of oropharyngeal cancer cell lines

Project description:mRNA sequencing was performed on oropharyngeal cancer cell lines including 4 HPV-positive and 4 HPV-negative lines. Two lines (CUOP2 and CUOP3) were newly derived from HPV-positive tonsil cancers (derivation is described in "Sensitivity to inhibition of DNA repair by Olaparib in novel oropharyngeal cancer cell lines infected with Human Papillomavirus" by Pirotte et al. This work was undertaken with the aims of quantifying levels of HPV gene transcription and identifying human:viral fusion transcripts arising from integrated viral sequences. We also wished to compare expression of genes involved in DNA damage responses between HPV positive and negative cell lines. The published analyses showed expression of HPV encoded genes in all of the HPV-positive cell lines, and the presence of fusion transcripts derived from integrated virus. We did not identify any obvious correlation between expression of DNA repair genes and HPV status.

2018-11-28 | GSE123029 | GEO

A 13-gene signature prognostic of HPV-negative OSCC: discovery and external validation

Project description:OSCC is associated with substantial mortality and morbidity. In this study, we built on our previous molecular work to identify and validate a prognostic 13-gene signature that showed a higher ability than tumor stage in predicting survival for patients with HPV-negative oral squamous cell carcinoma (OSCC). We previously reported 131 genes to be associated with survival in OSCC patients. In this study, we applied L1/L2-penalized Cox regression models to the Affymetrix array data from 97 HPV-negative OSCC patients on the 131 gene to identify a model for prediction of OSCC-specific survival. We then tested the model in an independent dataset and compared to tumor stage.

2013-03-07 | E-GEOD-41613 | biostudies-arrayexpress

Determine differences in gene expression between OPSCC cell lines with different sensitivity to IR

Project description:mRNA sequencing was performed on 10 oropharyngeal cancer cell lines (5 HPV-positive and 5 HPV-negative cell lines) for this project. Two cell lines (CU-OP-17 and CU-OP-20) were newly derived from HPV-negative and HPV-positive tonsil cancers, respectively (described in " Sensitivity of human papillomavirus-positive and -negative oropharyngeal cancer cell lines to ionizing irradiation" by Holzhauser et al. This study was performed with the goal to identify differences in gene expression between irradiated and non-irradiated cell line samples. Additionally, the aim was to identify possible changes in genes, involved in DNA repair or DNA damage response of the HPV-positive and HPV-negative cell lines. The data published showed an increase of HPV integration sites after irradiation. Additionally, all HPV-positive cell lines in this study showed expression of HPV encoded genes. However, no direct correlation of changes or expression of DNA repair genes was identified.

2020-07-08 | GSE153966 | GEO

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