Journal
GENOME MEDICINE
Volume 5, Issue -, Pages -Publisher
BIOMED CENTRAL LTD
DOI: 10.1186/gm453
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Funding
- UCLH/UCL NIHR Biomedical Research Centre (BRC)
- Wellcome Trust [WT093855MA, WT084071]
- Austrian Science Fund [J2856]
- Royal Society Wolfson Research Merit Award [WM100023]
- Cancer Research U.K.
- Austrian Science Fund (FWF) [J2856] Funding Source: Austrian Science Fund (FWF)
- Cancer Research UK [13100] Funding Source: researchfish
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Background: Human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) is an emerging disease, representing a distinct clinical and epidemiological entity. Understanding the genetic basis of this specific subtype of cancer could allow therapeutic targeting of affected pathways for a stratified medicine approach. Methods: Twenty HPV+ and 20 HPV-laser-capture microdissected oropharyngeal carcinomas were used for paired-end sequencing of hybrid-captured DNA, targeting 3,230 exons in 182 genes often mutated in cancer. Copy number alteration (CNA) profiling, Sequenom MassArray sequencing and immunohistochemistry were used to further validate findings. Results: HPV+ and HPV- oropharyngeal carcinomas cluster into two distinct subgroups. TP53 mutations are detected in 100% of HPV negative cases and abrogation of the G1/S checkpoint by CDKN2A/B deletion and/or CCND1 amplification occurs in the majority of HPV- tumors. Conclusion: These findings strongly support a causal role for HPV, acting via p53 and RB pathway inhibition, in the pathogenesis of a subset of oropharyngeal cancers and suggest that studies of CDK inhibitors in HPV- disease may be warranted. Mutation and copy number alteration of PI3 kinase (PI3K) pathway components appears particularly prevalent in HPV+ tumors and assessment of these alterations may aid in the interpretation of current clinical trials of PI3K, AKT, and mTOR inhibitors in HNSCC.
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