Somatic alterations, metabolizing genes and smoking in rectal cancer.
Somatic alterations, metabolizing genes and smoking in rectal cancer.
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DOI：
10.1002/ijc.24338
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发表时间：
2009-07-01
影响因子：
6.4
通讯作者：
Slattery, Martha L.
中科院分区：
文献类型：
--
作者：
Curtin, Karen;Samowitz, Wade S.;Wolff, Roger K.;Herrick, Jennifer;Caan, Bette J.;Slattery, Martha L.
吸烟已被确定为直肠癌的危险因素。我们的研究评估了直肠肿瘤中主动和被动吸烟与 TP53、KRAS2 和 BRAF V600E 突变、微卫星不稳定性 (MSI) 和 CpG 岛甲基化表型 (CIMP) 之间的关联。我们在一项基于人群的病例对照研究中研究了 GSTM1 和 NAT2 的遗传变异如何改变这些关联，该研究对 750 例直肠癌病例和 1201 例对照进行了研究。通过广泛的调查问卷收集了详细的烟草暴露数据。检查血液 DNA 中的 GSTM1 和 NAT2 变异。评估肿瘤 DNA 以确定 TP53（外显子 5-8）、KRAS2（密码子 12-13）和 BRAF 突变、MSI（BAT26 和 TGFβRII 分析）和 CIMP（CDKN2A、MLH1、MINT1、MINT2 和 MINT31 中 CpG 岛的甲基化）。吸烟（相对于不吸烟者，>20包年）与直肠肿瘤中TP53突变（OR=1.4，95%CI 1.02-2.0）、BRAF突变（OR=4.2，95%CI 1.3-14.2）和MSI（OR=5.7，95%CI 1.1-29.8）风险增加相关。每周>10小时的长期环境烟草烟雾（ETS）暴露与KRAS2突变风险增加相关（OR=1.5，95%CI 1.04–2.2）。所有吸烟指标均提示 CIMP+ 直肠癌风险增加。 GSTM1 和 NAT2 通常与直肠肿瘤改变无关；然而，我们观察到 ETS 和 NAT2 在 TP53 突变肿瘤中存在相互作用 (p<0.01)。我们的研究表明，主动吸烟与直肠肿瘤中 TP53、BRAF 和 MSI+ 风险增加相关，并提示 CIMP+ 肿瘤风险增加。 ETS 可能会增加 KRAS2 突变的风险； TP53 突变和 ETS 的关联可能受到 NAT2 的影响。
Cigarette smoking has been identified as a risk factor for rectal cancer. Our investigation evaluates associations between active and passive smoking and TP53, KRAS2, and BRAF V600E mutations, microsatellite instability (MSI), and CpG Island Methylator Phenotype (CIMP) in rectal tumors. We examine how genetic variants of GSTM1 and NAT2 alter these associations in a population-based, case-control study of 750 incident rectal cancer cases and 1201 controls. Detailed tobacco exposure data were collected in an extensive questionnaire. DNA from blood was examined for GSTM1 and NAT2 variants. Tumor DNA was assessed to determine TP53 (exons 5–8), KRAS2 (codons 12–13) and BRAF mutations, MSI (BAT26 and TGFβRII analysis), and CIMP (methylation of CpG islands in CDKN2A, MLH1, MINT1, MINT2, and MINT31). Cigarette smoking (>20 pack-years, relative to non-smokers) was associated with increased risk of TP53 mutations (OR=1.4, 95%CI 1.02–2.0), BRAF mutations (OR=4.2, 95%CI 1.3–14.2), and MSI (OR=5.7, 95%CI 1.1–29.8) in rectal tumors. Long-term environmental tobacco smoke (ETS) exposure of >10 hours/week was associated with increased risk of KRAS2 mutation (OR=1.5, 95%CI 1.04–2.2). All smoking indicators were suggestive of increased risk in CIMP+ rectal cancer. GSTM1 and NAT2 were generally not associated with rectal tumor alterations; however, we observed an interaction of ETS and NAT2 in TP53-mutated tumors (p<0.01). Our investigation shows active smoking is associated with increased risk of TP53, BRAF, and MSI+ in rectal tumors and is suggestive of increased risk of CIMP+ tumors. ETS may increase risk of KRAS2 mutations; association with TP53 mutations and ETS may be influenced by NAT2.
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