Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias.
Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias.
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DOI：
10.1093/carcin/bgn048
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发表时间：
2008-05
期刊：
影响因子：
4.7
通讯作者：
T. Kohno;H. Kunitoh;Kenji Suzuki;Seiichiro Yamamoto;A. Kuchiba;Y. Matsuno;N. Yanagitani;J. Yokota
中科院分区：
文献类型：
--
作者：
T. Kohno;H. Kunitoh;Kenji Suzuki;Seiichiro Yamamoto;A. Kuchiba;Y. Matsuno;N. Yanagitani;J. Yokota
肺腺瘤易感性1（Pas 1）基因影响小鼠肺腺瘤发展的易感性，其中一部分腺瘤进展为腺癌（ADC）。在这项研究中，10个多态性的基因型分布在人类对应的三个小鼠候选Pas 1基因，KRAS，CASC 1/LAS 1和LRMP，在医院为基础的病例对照研究包括364肺ADC病例和253对照。所有ADC病例均行肺叶切除术，随后进行非典型腺瘤样增生（AAH）的病理学检查，AAH是外周肺ADC的假定前体，包括切除肺叶中的细支气管肺泡癌。81例（22%）ADC病例除原发性ADC外至少有一处AAH病变，其中34例（9%）有多处AAH病变。10个基因多态性均未显示与肺ADC风险有显著相关性（P > 0.05）。然而，KRAS基因中两种多态性（KRAS-1和-6）的次要等位基因携带者显示ADC伴多发性AHH的比值比（OR）显著增加[OR = 3.0; 95%置信区间（CI）= 1.4-6.2，P = 0.004和OR = 2.4; 95% CI = 1.1-4.7，P = 0.02]。包括KRAS-6多态性的次要等位基因在内的次要单倍型显示ADC伴随多个AAH的OR增加，并且在肺组织中检测到来自该多态性的次要等位基因的KRAS转录物比来自主要等位基因的转录物更丰富。因此，KRAS多态性被证明参与了AAH发展的风险，AAH通过引起肺中KRAS癌基因的差异表达而进展为ADC。
The pulmonary adenoma susceptibility 1 (Pas1) gene affects susceptibility to the development of lung adenomas in mice with a subset of the adenomas progressing to adenocarcinoma (ADC). In this study, genotype distributions for 10 polymorphisms in the human counterparts for three mouse candidate Pas1 genes, KRAS, CASC1/LAS1 and LRMP, were examined in a hospital-based case-control study consisting of 364 lung ADC cases and 253 controls. All the ADC cases were subjected to lobectomy and subsequent pathological investigation of atypical adenomatous hyperplasia (AAH), a putative precursor for peripheral lung ADC, including bronchioloalveolar carcinoma, in the resected lobes. Eighty-one (22%) of the ADC cases carried at least one AAH lesion in addition to the primary ADC and 34 (9%) of them carried multiple AAH lesions. None of the 10 polymorphisms examined showed significant associations with overall lung ADC risk (P > 0.05). However, minor allele carriers for two polymorphisms in the KRAS gene, KRAS-1 and -6, showed significantly increased odds ratios (ORs) for ADC accompanied by multiple AAHs [OR = 3.0; 95% confidence interval (CI) = 1.4-6.2, P = 0.004 and OR = 2.4; 95% CI = 1.1-4.7, P = 0.02, respectively]. Minor haplotypes including the minor allele for the KRAS-6 polymorphism showed increased ORs for ADC accompanied by multiple AAHs, and KRAS transcripts from the minor allele for this polymorphism were more abundantly detected in lung tissues than those from the major allele. Thus, KRAS polymorphisms were indicated to be involved in risk for the development of AAHs that progress to ADC by causing differential KRAS oncogene expression in the lungs.