Smoking–genomic discordance in metastatic non–small cell lung cancer.

作者：Ilit Turgeman, Federica Pecci, Yakatherina Shulman, Kirill Drozdov, P A Jänne · 发表于：Journal of Clinical Oncology · 年份：2026 · DOI：10.1200/jco.2026.44.16_suppl.8543 · 研究领域：Lung Cancer Treatments and Mutations、Cancer Genomics and Diagnostics、Lung Cancer Research Studies

8543 Background: Smoking is the dominant risk factor for lung cancer, yet clinical smoking history does not consistently align with the presence of tobacco-associated mutational patterns (C > A transversions). We hypothesized that smoking-genomic discordance identifies a biologically distinct subset of tumors arising through endogenous, aging-enriched mutational processes. Methods: We analyzed metastatic NSCLC patients with documented smoking history and tumor sequencing from a discovery cohort (n = 111) and an independent Dana-Farber validation cohort (n = 2,680). Tumors were stratified by presence or absence of C > A tobacco transversions. Endpoints included C > T transition burden as a surrogate for aging-related mutational processes, transition-to-transversion (Ti/Tv) ratio for endogenous mutational contribution, tumor mutational burden (TMB), oncogenic driver distribution, and first line treatment outcomes. Multivariable regression models adjusted for age, sex, smoking intensity, and driver genotype. Results: Among patients with smoking history, 30% of the discovery and 15.2% of the validation cohort lacked detectable C > A transversions, including 29% with > 30 pack-years. Smoking intensity correlated with C > A but not C > T burden, while C > T increased with age in binomial models, consistent with clock-like aging accumulation. C > A negative discordant tumors had higher C > T fractions and Ti/Tv ratios than both concordant smokers and ne...