Smoking has historically been recognized as a negative prognostic factor in head and neck squamous cell carcinoma (HNSCC). This study aimed to assess the mutational differences between heavy smokers (>20 pack-years) and never smokers among the HNSCC patients within The Cancer Genome Atlas (TCGA). Single nucleotide variation (SNV) and copy number aberration (CNA) differences between heavy smokers and never smokers were compared within HPV-positive (n=67) and negative (n=431) TCGA HNSCC cohorts, and the impact of these mutations on survival was assessed. No genes were differentially mutated between smoking and never smoking patients with HPV-positive tumors. By contrast, in HPV-negative tumors, NSD1 and COL1A11 were found to be more frequently mutated in heavy smokers, while CASP8 was more frequently altered in never smokers. HPV-negative patients with NSD1 mutations experienced significantly improved overall survival compared with NSD1 wild-type patients. This improved prognosis was validated in an independent cohort of 77 oral cavity cancers and a meta-analysis that included two additional datasets (688 total patients, hazard ratio for death 0.44, 95% CI 0.30-0.65). NSD1 mutations are more common in HPV-negative heavy smokers and define a cohort with favorable prognosis, and may represent a clinically useful biomarker to guide treatment deintensification for HPV-negative patients.

Citation Format: Farhad Ghasemi, Stephenie D. Prokopec, Danielle MacNeil, Neil Mundi, Christopher Howlett, William Stecho, Kevin Fung, John Yoo, Eric Winquist, Steven Gameiro, Axel Sahovaler, Paul Plantinga, Joe S. Mymryk, John W. Barrett, Paul C. Boutros, Anthony C. Nichols. Mutational analysis of head and neck squamous cell carcinoma stratified by smoking status [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr PR02.