You Ming, Wang Daolong, Liu Pengyuan, Vikis Haris, James Michael, Lu Yan, Wang Yian, Wang Min, Chen Qiong, Jia Dongmei, Liu Yan, Wen Weidong, Yang Ping, Sun Zhifu, Pinney Susan M, Zheng Wei, Shu Xiao-Ou, Long Jirong, Gao Yu-Tang, Xiang Yong-Bing, Chow Wong-Ho, Rothman Nat, Petersen Gloria M, de Andrade Mariza, Wu Yanhong, Cunningham Julie M, Wiest Jonathan S, Fain Pamela R, Schwartz Ann G, Girard Luc, Gazdar Adi, Gaba Colette, Rothschild Henry, Mandal Diptasri, Coons Teresa, Lee Juwon, Kupert Elena, Seminara Daniela, Minna John, Bailey-Wilson Joan E, Amos Christopher I, Anderson Marshall W
Washington University, St. Louis, Missouri 63110, USA.
Clin Cancer Res. 2009 Apr 15;15(8):2666-74. doi: 10.1158/1078-0432.CCR-08-2335. Epub 2009 Apr 7.
We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP).
Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members.
A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels.
RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.
我们之前已将一个影响家族性肺癌风险的主要易感基因座定位到6号染色体的6q23 - 25区域。然而，该基因座上的致病基因仍未确定。在本研究中，我们通过使用微卫星标记进行精细定位以及使用高密度单核苷酸多态性（SNP）进行关联研究，进一步细化该基因座以确定单个候选基因。
选择六个有五个或更多患病成员的多代家族，使用微卫星标记对6q连锁区域进行精细定位。对于关联定位，我们使用Affymetrix 500K芯片组对来自肺癌遗传流行病学联盟资源的24例6q连锁病例和72例无关的非癌症对照进行基因分型。在两个独立的家族性肺癌群体中验证了显著关联：来自肺癌遗传流行病学联盟的226例家族性肺癌病例和313例对照，以及来自梅奥诊所的154例家族性病例和325例对照。每个家族性病例均选自一个有三个或更多患病成员的高危肺癌家族。
对6q23 - 25区域进行全区域扫描发现，肺癌易感性与RGS17基因第一内含子中的三个单核苷酸多态性之间存在显著关联。这种关联在两个独立的家族性肺癌群体中得到进一步证实。通过对匹配的肿瘤和正常人体组织进行定量实时PCR分析，我们发现RGS17转录本积累在散发性肺癌中高度且持续增加。敲低RGS17水平可抑制人肺肿瘤细胞增殖和裸鼠肿瘤发生。
RGS17是6号染色体6q23 - 25上家族性肺癌易感基因座的主要候选基因。
