Genetic Susceptibility of Lung Cancer Associated With Common Variants in the 3′ Untranslated Regions of the Adenosine Triphosphate-Binding Cassette B1 (ABCB1) and ABCC1 Candidate Transporter Genes for Carcinogen Export
Genetic Susceptibility of Lung Cancer Associated With Common Variants in the 3′ Untranslated Regions of the Adenosine Triphosphate-Binding Cassette B1 (ABCB1) and ABCC1 Candidate Transporter Genes for Carcinogen Export
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DOI：
10.1002/cncr.24042
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发表时间：
2009-02-01
期刊：
影响因子：
6.2
通讯作者：
Lu, Daru
中科院分区：
文献类型：
--
作者：
Wang, Haijian;Jin, Guangfu;Lu, Daru
背景：烟草特有的亚硝胺4-(甲基亚硝胺)-1-(3-吡啶基)-1-丁酮(NKK)是一种明确的致癌物质，可诱发肺癌。其处置途径中的基因多态性可能会改变患肺癌的风险。该报告的作者此前对中国人群中致癌物质输出的三磷酸腺苷结合盒B1（ABCB1）和ABCC1候选转运蛋白基因的序列变异进行了分类，并筛选出了其5'侧翼和3'非翻译区具有潜在功能的常见变异。本研究的目的是检验这些常见变异与肺癌风险相关的假设，方法：对 6 个常见调控变异进行基因分型分析（参考单核苷酸多态性 4728709 [rs4728709] 和 ABCB1 5' 侧翼区域的 rs2188524 和 3' 非翻译区域的 rs3842；rs3743527， rs212090 和 rs212091（位于 ABCC1 3' 非翻译区）是在一项病例对照研究中进行的，该研究纳入了中国人群中的 500 名肺癌患者和 517 名无癌症对照者。结果：与野生腺苷/腺苷（A/A）基因型相比，ABCB1的变异rs3842基因型（腺苷/鸟苷[A/G] + G/G）与患肺癌的风险显着增加相关（比值比[OR]. 1.36；95%置信区间[95% CI], 1.06-1.76）。同样明显的是癌症易感性与 ABCC1 的变异 rs212090 基因型（腺苷/胸苷 [A/T] + T/T）之间的关联（OR，1.37；95% CI，1.03-1.83）。基于单元型的关联分析还强调，携带 2 个单核苷酸多态性的罪魁祸首等位基因的 2 个常见单元型与癌症风险增加相关。此外，分层分析表明 ABCB1 rs3842 与女性（OR，2.57；95% CI，1.36-4.85）、腺癌组织学类型（OR，1.42；95% CI，1.03-1.99）和年龄 < 60 岁个体（OR，1.50；95% CI，1.36-4.85）的癌症风险显着相关。 95% CI，1.05-2.14）。结论：目前的研究表明，ABCB1 和 ABCC1 3'非翻译区的常见多态性可能与肺癌的病因学有关，这为 NNK 代谢和处置中的遗传成分可能改变肺癌风险（尤其是女性肺腺癌）的假设提供了进一步的支持。需要进行功能研究来阐明用于致癌物输出的 ABC 转运蛋白的异常表达和功能障碍是否可能在肺癌的发展中发挥作用。癌症 2009；115：595-607。 (c) 2008 年美国癌症协会。
BACKGROUND: Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NKK) is a well defined carcinogen that can induce lung cancer. Genetic polymorphisms in its disposition pathways could modify the risk of developing lung cancer. The authors of this report previously catalogued the sequence variations of the adenosine triphosphate-binding cassette B1 (ABCB1) and ABCC1 candidate transporter genes for carcinogen export in the Chinese population and screened out common variants with potential function in their 5' flanking and 3' untranslated regions. The objective of the current study was to test the hypothesis that these common variants are associated with lung cancer risk, METHODS: The genotyping analyses for 6 common regulatory variants (reference single-nucleotide polymorphism 4728709 [rs4728709] and rs2188524 in the 5' flanking region of ABCB1 and rs3842 in its 3' untranslated region; rs3743527, rs212090, and rs212091 in the 3' untranslated region of ABCC1) was conducted in a case-control study of 500 patients with incident lung cancer and 517 cancer-free controls in a Chinese population. RESULTS: Compared with the wild adenosine/adenosine (A/A) genotype, the variant rs3842 genotype (adenosine/guanosine [A/G] + G/G) of ABCB1 was associated with a statistically significant increased risk of developing lung cancer (odds ratio [OR]. 1.36; 95% confidence interval [95% CI], 1.06-1.76). Also evident was the association between cancer susceptibility and the variant rs212090 genotype (adenosine/thymidine [A/T] + T/T) of ABCC1 (OR, 1.37; 95% CI, 1.03-1.83). Haplotype-based association analysis also emphasized that 2 common haplotypes carrying the culprit alleles of the 2 single-nucleotide polymorphisms were associated with an increased risk of cancer. In addition, stratification analysis demonstrated a remarkable association of ABCB1 rs3842 with the risk of cancer manifested in women (OR, 2.57; 95% CI, 1.36-4.85), in the histologic type of adenocarcinoma (OR, 1.42; 95% CI, 1.03-1.99), and in individuals aged < 60 years (OR, 1.50; 95% CI, 1.05-2.14). CONCLUSIONS: The current study demonstrated that common polymorphisms in the 3' untranslated region of ABCB1 and ABCC1 may contribute to the etiology of lung cancer, providing further support for the hypothesis that genetic components in the metabolism and the disposition of NNK may modify the risk of lung cancer, especially in lung adenocarcinoma among women. Functional studies are warranted to elucidate whether aberrant expression and dysfunction of ABC transporters for carcinogen export may play a role in the development of lung cancer. Cancer 2009;115:595-607. (c) 2008 American Cancer Society.