Faculty, Staff and Student Publications

Language

English

Publication Date

1-1-2025

Journal

BMJ Oncology

DOI

10.1136/bmjonc-2025-000787

PMID

40519220

PMCID

PMC12164326

PubMedCentral® Posted Date

6-3-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Objective: To test the hypothesis that the association of smoking with long-term colorectal cancer incidence may be stronger for tumours with higher mutational and neoantigen loads.

Methods and analysis: In the Nurses' Health Study (1980-2012) and the Health Professionals Follow-up Study (1986-2012), our novel prospective cohort incident-tumour biobank method (PCIBM) used 3053 incident colorectal carcinoma cases including 752 cases with whole-exome sequencing data. Using the multivariable duplication-method Cox regression model with the inverse probability weighting to adjust for the selection bias due to tissue availability, we assessed a differential association of cigarette smoking with colorectal carcinoma incidence by an exome-wide tumour mutational burden (e-TMB) or neoantigen load.

Results: The association of pack-years smoked with colorectal cancer incidence differed by e-TMB (Pheterogeneity< 0.001). Multivariable-adjusted HRs for e-TMB-high (≥10 mutations/megabase) tumours were 1.28 (95% CI 0.72 to 2.28) and 2.56 (95% CI 1.61 to 4.07) for 1-19 and ≥20 pack-years (vs 0 pack-years; Ptrend< 0.001), respectively. In contrast, pack-years smoked were not associated with e-TMB-low tumour incidence (Ptrend=0.67). A similar differential association was observed for the neoantigen load (Pheterogeneity=0.017). The differential association by e-TMB appeared consistent in the strata of CpG island methylator phenotype status, BRAF mutation or lymphocytic infiltrates.

Conclusions: Smoking is more strongly associated with the long-term incidence of colorectal carcinoma harbouring higher mutational and neoantigen loads. Our PCIBM-based evidence supports the immunosuppressive effect of smoking and the potential of smoking cessation in improving antitumour immunity for cancer prevention and treatment.

Keywords

Colorectal cancer, Epidemiology, Genetic markers, Immunogenicity, Tumour biomarkers

Published Open-Access

yes

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