Hamada Tsuyoshi, Ugai Tomotaka, Gurjao Carino, Ugai Satoko, Zhang Xuehong, Haruki Koichiro, Takashima Yasutoshi, Akimoto Naohiko, Lau Mai Chan, Matsuda Kosuke, Nakazawa Nobuhiro, Higashioka Mayu, Miyahara Satoshi, Kosumi Keisuke, Masugi Yohei, Liu Li, Cao Yin, Nevo Daniel, Wang Molin, Nishihara Reiko, Shukla Sachet A, Wu Catherine J, Garraway Levi A, Meyerhardt Jeffrey A, Giovannucci Edward L, Nowak Jonathan A, Fuchs Charles S, Chan Andrew T, Song Mingyang, Giannakis Marios, Ogino Shuji
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
BMJ Oncol. 2025 Jun 3;4(1):e000787. doi: 10.1136/bmjonc-2025-000787. eCollection 2025.
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.
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.
The association of pack-years smoked with colorectal cancer incidence differed by e-TMB (P<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; P<0.001), respectively. In contrast, pack-years smoked were not associated with e-TMB-low tumour incidence (P=0.67). A similar differential association was observed for the neoantigen load (P=0.017). The differential association by e-TMB appeared consistent in the strata of CpG island methylator phenotype status, mutation or lymphocytic infiltrates.
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.
检验以下假设，即对于具有更高突变和新抗原负荷的肿瘤，吸烟与长期结直肠癌发病率之间的关联可能更强。
在护士健康研究（1980 - 2012年）和卫生专业人员随访研究（1986 - 2012年）中，我们新颖的前瞻性队列发病肿瘤生物样本库方法（PCIBM）纳入了3053例结直肠癌发病病例，其中752例有全外显子测序数据。使用多变量重复法Cox回归模型并采用逆概率加权来调整因组织可获得性导致的选择偏倚，我们通过全外显子组肿瘤突变负荷（e - TMB）或新抗原负荷评估吸烟与结直肠癌发病率之间的差异关联。
按e - TMB分层，吸烟包年数与结直肠癌发病率的关联存在差异（P<0.001）。对于e - TMB高（≥10个突变/兆碱基）的肿瘤，多变量调整后的风险比在1 - 19包年和≥20包年时分别为1.28（95%可信区间0.72至2.28）和2.56（95%可信区间1.61至4.07）（与0包年相比；P<0.001）。相比之下，吸烟包年数与e - TMB低的肿瘤发病率无关（P = 0.67）。对于新抗原负荷也观察到类似的差异关联（P = 0.017）。按e - TMB的差异关联在CpG岛甲基化表型状态、突变或淋巴细胞浸润分层中似乎是一致的。
吸烟与具有更高突变和新抗原负荷的结直肠癌长期发病率的关联更强。我们基于PCIBM的证据支持吸烟的免疫抑制作用以及戒烟在改善抗肿瘤免疫以预防和治疗癌症方面的潜力。
