Genomic profiling of kinase genes in head and neck squamous cell carcinomas to identify potentially targetable genetic aberrations in FGFR1/2, DDR2, EPHA2, and PIK3CA.

Abstract

6010 Background: Development of targeted therapies in head and neck squamous cell carcinoma (HNSCC) has been limited due to the lack of validated, oncogenic genetic aberrations. We determined mutations and copy number (CN) events in kinases in a 120 patient cohort in order to identify new potential treatment targets. Methods: Fresh frozen tumor (≥70%) and matched normal tissue from 120 patients with treatment-naïve, locoregionally advanced HNSCC were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 60 cancer-relevant, targetable kinases (as well as PI3K related tumor suppressors). CN analysis was performed on the NanoString nCounter for 40 cancer relevant kinases. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC. Results: We identified somatic mutations in three potentially targetable receptor tyrosine kinases: 7 (5.8%) mutations were identified in DDR2, 3 (2.5%) mutations in FGFR2, and 4 (3.3%) mutations in EPHA2. Furthermore we identified multiple mutations in several PI3K family members including PIK3CA (N=22 (18,3%)) as well as PI3K related tumor suppressors (PTEN N=3 (2.5%)), INPP4B N=7 (5.8%)). Several mutations showed low CHASM scores consistent with oncogenic driver characteristics. We identified recurrent copy number aberrations in two kinases – FGFR1 (N=15 (13%), median CN:3.27 (3.03-15.662)), and EGFR (N=13 (11%), median CN: 3.73 (2.93-17.75)). Interestingly similar mutations/copy number events have been described in other cancer types including endometrial, and lung squamous cell carcinomas. Conclusions: We identified multiple novel mutations and copy number events in 45% of tumors: genetic aberration in FGFR1, FGFR2, DDR2, EPHA2, and the PI3K pathway are candidate oncogenic drivers that are potentially targetable. Results are corroborated by similar aberrations in other cancer types e.g. lung squamous cell carcinomas that are already being explored as therapeutic targets. Further validation and initiation of focused clinical trials in mutation pre-selected patients is indicated.