Smoking habit and long-term colorectal cancer incidence by exome-wide mutational and neoantigen loads: evidence based on the prospective cohort incident-tumour biobank method

Smoking habit and long-term colorectal cancer incidence by exome-wide mutational and neoantigen loads: evidence based on the prospective cohort incident-tumour biobank method

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), o...

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Main Authors: Li Liu, Andrew T Chan, Jeffrey A Meyerhardt, Xuehong Zhang, Mingyang Song, Molin Wang, Shuji Ogino, Charles S Fuchs, Edward L Giovannucci, Yin Cao, Mayu Higashioka, Reiko Nishihara, Yohei Masugi, Marios Giannakis, Koichiro Haruki, Mai Chan Lau, Tomotaka Ugai, Naohiko Akimoto, Jonathan A Nowak, Levi A Garraway, Tsuyoshi Hamada, Catherine J Wu, Daniel Nevo, Carino Gurjao, Satoko Ugai, Yasutoshi Takashima, Kosuke Matsuda, Nobuhiro Nakazawa, Satoshi Miyahara, Keisuke Kosumi, Sachet A Shukla
Format: Article
Language:English
Published: BMJ Publishing Group 2025-06-01
Series:BMJ Oncology
Online Access:https://bmjoncology.bmj.com/content/4/1/e000787.full
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Summary: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.
ISSN:2752-7948

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