Abstract 1117: Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in the Cancer Genome Atlas.
Authors: Hayes David N. , Grandis Jennifer , El-Naggar Adel K. 
Published: August 2014

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the leading causes of cancer death in the United States and Worldwide. Most cancers are tobacco-related, although an increasing number of tumors are found in nonsmokers in association with the human papilloma virus (HPV).

Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays on surgically resected samples from previously untreated patients with HNSCC. We report for the first time the results for 279 HNSCC samples for whom complete data are available.

Results: The demographics of 279 patients enrolled in the study documented a median age of 61 years (range: 19-90); 27% female, and history of tobacco smoking in 80%. Over 30 sites of significant somatic copy number alteration (SCNA) were identified, most of which were shared with recently reported alterations in lung squamous cell carcinoma. However, some notable SCNA were absent in HNSCC: PDGFRA amplification and deletion of FOXP. Similarly, SCNA were compared between HPV + and HPV - tumors identifying numerous differences, including a paucity of receptor tyrosine kinase alterations in HPV + tumors and novel deletions in chromosome 11q and 14q. Exome sequencing revealed at least 15 significantly mutated genes at the False Discovery Rate (FDR) of &lt;0.01, including: CDKN2A, TP53, PIK3CA, FAT1, MLL2, TGFBR2, HLA-A, NOTCH1, HRAS, NFE2L2, and CASP8. Consideration of differences between HPV + and HPV - tumors suggested differences which included nearly universal alteration of TP53 and frequent p16 mutations in HPV - tumors. By contrast, few TP53 or CDKN2A mutations were observed in HPV + samples. Strikingly, a large number of co-occurring genomic alterations were observed. For example, mutations of HRAS were observed nearly universally in combination with either CASP8 or FAT1. All three of these mutations were absent in HPV + patients. mRNA expression profiling revealed four distinct expression subtypes, each one enriched with distinct SCNA and mutational profiles: classical, basal, mesenchymal, and atypical. Deep sequencing by multiple platforms allowed for a detailed accounting of the role of HPV in alterations of the cancer genomes of HNSCC patients, including integration sites, disruption of tumor suppressor genes, and more complex rearrangements. Potential therapeutic targets for clinical trials with currently available drugs will be discussed.

Conclusions: HNSCC is a heterogeneous tumor which displays distinctive patterns of somatic alteration potentially amenable to molecularly targeted therapies. We document for the first time using TCGA data, the role of an oncogenic virus in the human cancer genome. Results presented on behalf of TCGA.

Citation Format: David N. Hayes, Jennifer Grandis, Adel K. El-Naggar. Comprehensive genomic characterization of squamous cell carcinoma of the head and neck in the Cancer Genome Atlas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1117. doi:10.1158/1538-7445.AM2013-1117