Genetic and Molecular Differences in Head and Neck Cancer Based on Smoking History.

Importance: Up to 80% of survivors of head and neck squamous cell carcinoma (HNSCC) currently or previously smoked. Thus, tobacco use is a major modifiable risk factor for HNSCC, even in the era of human papillomavirus (HPV)-associated disease. However, how smoking underlies chromosomal and epigenetic changes that are associated with HNSCC outcomes remains unclear.

Objective: To characterize genetic and molecular differences and associated biological pathways in patients with HNSCC based on smoking history.

Design, setting, and participants: This retrospective cohort study included patients with a confirmed diagnosis of HNSCC from the Cancer Genome Atlas via cBioPortal data independent of HPV status. Data were analyzed between April 2023 and May 2024.

Main outcomes and measures: Smoking history was defined as individuals who smoked (currently or previously) compared with nonsmokers (never smoked). Genetic and molecular differences of interest were single nucleotide variation, copy number alteration, DNA methylation, and messenger RNA (mRNA) expression. Accounting for multiple testing, we reported the false discovery rate (FDR), with a statistically significant FDR of 0.05 or less. Potential functions and pathways were investigated using the Panther classification system, and the Fisher exact test was used for overrepresentation, using the Reactome pathway dataset as a guide. Associations between smoking-related genetic alterations and overall survival were analyzed using log-rank tests.

Results: Of 511 participants, 135 (26.4%) were female, and the mean (SD) age was 60.8 (11.9) years. People who smoked (389 [76.1%]) demonstrated significantly enriched copy number alterations on 9 genes located on chromosome 11q13 compared with nonsmokers (122 [23.9%]; FDR, 0.044-0.046). Two genes, FADD and CTTN, were significantly highly methylated in nonsmokers. Also, PPFIA1, FGF19, CCND1 and LTO1 were highly expressed in mRNA in those who smoked, while FADD mRNA expression was negatively correlated with FADD DNA methylation in nonsmokers (Pearson r = -0.53; 95% CI, -0.59 to -0.49) and those who smoked (Pearson r = -0.57; 95% CI, -0.63 to -0.51). People who smoked with altered FADD had higher risk of dying than those with FADD unaltered (hazard ratio, 1.40; 95% CI, 1.004-1.96). Pathway analysis showed the significant genes were collectively associated with cellular processes and biological regulations, including olfactory signaling and the PI3K/AKT network.

Conclusion and relevance: The results of this cohort study suggest that there may be patterned genetic and molecular differences in patients with HNSCC based on smoking history, especially genes located on chromosome 11q13. These genomic differences due to smoking make smoking a modifiable risk factor for HNSCC outcomes.