Genetic Susceptibility for Head and Neck Cancer Related to Air Pollution Exposure

Introduction: There are known genetic and environmental determinants of Head and Neck Cancers (HNC), but gene-environment interactions are poorly studied. We tested the role of genetic variation in the association between exposure to ambient particulate matter (≤2.5 micrometers in diameter [PM2.5]) and diagnosis of HNC.

Methods: We determined PM2.5 air pollution exposure in adult participants in the NIH All of Us (AoU) research program using validated spatiotemporal models (1-9 years windows at home address [3-digit zip code]). We then used logistic regression to test the relationships between PM2.5 level and HNC (physician diagnosis and clinical visits, presence of a follow up visit, and CT scan of the head and neck from linked HER data), adjusting for age, sex, race, education, median income, health insurance, smoking/alcohol use, self-rated physical health, and HPV (p16 detection). In parallel, we performed a GWAS (genotyping by Single Nucleotide Polymorphism chip, 9710328 SNPs) in 906 adults with HNC and 4310 controls in AoU, adjusting for age, sex, and race to identify HNC-associated SNPs. Finally, we determined the role of these SNPs in the PM2.5 exposure-HNC relationship.

Results: AoU adults with higher long term PM2.5 exposure were significantly more likely to be diagnosed with HNC (1 year exposure window: OR = 1.02, 95% CI 1.00, 1.06, p = 0.04, per 1µg/m³ increase in PM2.5; 9 year: OR = 1.13, 95% CI 1.02, 1.30, p < 0.01). SNPs in LDLRAP1 (p < 0.01, interaction term), AC079465.1, MCC, TSSK1B (p < 0.01), SETBP1 (p < 0.01), YTHDC2 (p < 0.01), AL669970.3 (p < 0.01), FNDC3A (p = 0.02) mediated this relationship. We did not find any significant mediation effects for other genetic variants.

Conclusions: Long-term airborne PM2.5 exposure increases odds of diagnosis of HNC, and individuals who harbor variants in the LDLRAP1, AC079465.1, MCC, TSSK1B, SETBP1, YTHDC2, AL669970.3, FNDC3A loci face increased odds. Understanding how genetic variation results in susceptibility to HNC upon air pollution exposure could improve targeted interventions.