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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2025-06-01
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| Series: | BMJ Oncology |
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| author | 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 |
| author_facet | 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 |
| author_sort | Li Liu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dd2057ffc1e045c397d211804fd33e87 |
| institution | OA Journals |
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| language | English |
| publishDate | 2025-06-01 |
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| series | BMJ Oncology |
| spelling | doaj-art-dd2057ffc1e045c397d211804fd33e872025-08-20T02:24:25ZengBMJ Publishing GroupBMJ Oncology2752-79482025-06-014110.1136/bmjonc-2025-000787Smoking habit and long-term colorectal cancer incidence by exome-wide mutational and neoantigen loads: evidence based on the prospective cohort incident-tumour biobank methodLi Liu0Andrew T Chan1Jeffrey A Meyerhardt2Xuehong Zhang3Mingyang Song4Molin Wang5Shuji Ogino6Charles S Fuchs7Edward L Giovannucci8Yin Cao9Mayu Higashioka10Reiko Nishihara11Yohei Masugi12Marios Giannakis13Koichiro Haruki14Mai Chan Lau15Tomotaka Ugai16Naohiko Akimoto17Jonathan A Nowak18Levi A Garraway19Tsuyoshi Hamada20Catherine J Wu21Daniel Nevo22Carino Gurjao23Satoko Ugai24Yasutoshi Takashima25Kosuke Matsuda26Nobuhiro Nakazawa27Satoshi Miyahara28Keisuke Kosumi29Sachet A Shukla30Telemedicine Center, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, ChinaDivision of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA8 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USAassociate professorassociate professor6 Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USA10 Yale Cancer Center, New Haven, Connecticut, USAprofessorpostdoctoral research fellowDepartment of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, JapanProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women`s Hospital and Harvard Medical School, Boston, Massachusetts, USA4 Department of Pathology, Keio University School of Medicine, Tokyo, JapanDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA3Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore6 Department of Epidemiology, Harvard University T.H. Chan School of Public Health, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women`s Hospital and Harvard Medical School, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women`s Hospital and Harvard Medical School, Boston, Massachusetts, USA1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USADepartment of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan2Dana-Farber Cancer Institute, Boston, MA, USADepartment of Statistics and Operations Research, Tel Aviv University, Tel Aviv, IsraelDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USAProgram in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USADepartment of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAObjective 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.https://bmjoncology.bmj.com/content/4/1/e000787.full |
| spellingShingle | 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 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 BMJ Oncology |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | https://bmjoncology.bmj.com/content/4/1/e000787.full |
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