Genetic Liability to Smoking and Alcohol Use in Head and Neck Squamous Cell Carcinoma Risk and Survival: Towards A Personalized Approach

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Abstract
Background: Polygenic risk scores (PRS) can provide a proxy for genetic liability to smoking- and alcohol-related behaviors. If these behavior-associated PRS can also predict the risk or survival of head and neck squamous cell carcinoma (HNSCC), then such PRS can provide motivation for behavioral modification during counseling by associating behavior with its consequences.Methods: Based on the VOYAGER Consortium of 3,254 controls and 5,538 HNSCC cases, where 3,194 were HPV-positive, we constructed PRS for multiple smoking and alcoholic metrics, using summary statistics from GSCAN. We evaluated the HPV-stratified HNSCC risk by logistic regression, overall survival by Cox models comparing different percentile strata of PRS and compared these results to observed behaviors.Findings: Each higher PRS predicted greater corresponding smoking and alcohol use behaviors. For HPV-positive diseases, higher PRS for smoking initiation and alcoholic drinks-per-week predicted increased HNSCC risk. Similarly, higher PRS for smoking initiation, cigarettes-per-day, smoking cessation, and alcoholic drinks-per-week each predicted higher HPV-negative HNSCC risk. For overall survival, higher PRS of smoking initiation (HR = 1.08, P=0.017) and alcoholic drinks-per-week (HR=1.14, P=2.66×10-4) predicted poorer prognosis in HPV-positive cases. Illustrative models showed similar results for a genetic counseling purpose. Each PRS predicted its corresponding observed behavior which mediated part of the associations (7.30%-54.6%) between PRSs and HNSCC risk or survival.Interpretation: Smoking- and alcohol-related PRS predicted observed behaviors, greater HNSCC risk and poorer overall survival. These findings support integrating genetic liability with clinical factors to refine counseling strategies for behavior modification.