Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
Clin Cancer Res. 2021 Jul 1;27(13):3725-3733. doi: 10.1158/1078-0432.CCR-20-4419. Epub 2021 Apr 13.
Exome- and whole-genome sequencing of muscle-invasive bladder cancer has revealed important insights into the molecular landscape; however, there are few studies of non-muscle-invasive bladder cancer with detailed risk factor information.
We examined the relationship between smoking and other bladder cancer risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in bladder cancer was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RR) and 95% CIs, evaluating signatures and risk factors.
Non-silent mutations were more common in females than males (OR = 1.83; 95% CI, 1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater Signature mutations compared with former ( = 0.024) and never smoking (RR = 1.40; 95% CI, 1.09-1.80; = 0.008), former smoking was associated with greater APOBEC-Signature13 mutations ( = 0.05), and never smoking was associated with greater APOBEC-Signature2 mutations (RR = 1.54; 95% CI, 1.17-2.01; = 0.002). There was evidence that smoking duration (the component most strongly associated with bladder cancer risk) was associated with Signature mutations and APOBEC-Signature13 mutations among current ( = 0.005) and former smokers ( = 0.0004), respectively.
These data quantify the contribution of bladder cancer risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.
对肌层浸润性膀胱癌进行外显子组和全基因组测序，揭示了其分子特征的重要见解；然而，很少有研究对具有详细风险因素信息的非肌层浸润性膀胱癌进行研究。
我们研究了吸烟和其他膀胱癌风险因素与膀胱癌肿瘤中的体细胞突变和突变特征之间的关系。在一项基于人群的病例对照研究中，对 322 例福尔马林固定石蜡包埋膀胱癌肿瘤进行了膀胱癌中经常发生突变的基因的靶向测序。使用逻辑回归计算优势比（OR）和 95%置信区间（CI），评估突变和风险因素。我们使用 SignatureEstimation 提取四个已知的单碱基替换突变特征，并使用泊松回归计算风险比（RR）和 95%CI，评估特征和风险因素。
非沉默性突变在女性中比男性更常见（OR=1.83；95%CI，1.05-3.19）。吸烟状况与已建立的单碱基替换特征之间的关系存在显著异质性：与以前（ = 0.024）和从不吸烟（RR=1.40；95%CI，1.09-1.80； = 0.008）相比，当前吸烟状态与更大的 Signature 突变相关，以前吸烟与更大的 APOBEC-Signature13 突变相关（ = 0.05），而从不吸烟与更大的 APOBEC-Signature2 突变相关（RR=1.54；95%CI，1.17-2.01； = 0.002）。有证据表明，吸烟时间（与膀胱癌风险关系最密切的因素）与当前吸烟者（ = 0.005）和以前吸烟者（ = 0.0004）中的 Signature 突变和 APOBEC-Signature13 突变相关。
这些数据量化了膀胱癌风险因素对突变负担的贡献，并表明从不吸烟者、以前吸烟者和当前吸烟者中存在不同的特征富集。
