biostudies-literatureYou MIntramural NIH HHSNIDCR NIH HHSNIEHS NIH HHSNHGRI NIH HHSNCI NIH HHS2666-74https://www.ebi.ac.uk/biostudies/studies/S-EPMC2746091biostudies-literatureUnknown15(8)<h4>Purpose</h4>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).<h4>Experimental design</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.Clinical cancer research : an official journal of the American Association for Cancer ResearchFine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.PMC2746091R01 CA099147N01HG65404R01 CA099187R01 CA080127U01CA76293P30CA 15083P50 CA070907P50 CA070907-03S29001R01ES012063R01 ES013340P30 CA022453R01 CA058554R01 CA093643U01 CA076293-09R01CA80127R01CA058554U01 CA076293N01-PC35145DE-FGB-95ER62060N01PC35145R03 CA077118P30CA22453P30 CA015083R01ES013340R01 CA063700P30ES06096P30 ES006096R01 ES012063R01CA093643R01CA63700R01CA099187P50CA70907R01CA099147Wiest JSJia DRothschild HLu YLong JWang DLiu PLee JSeminara DWen WVikis HWang MAmos CILiu YRothman NJames MFain PRGao YTAnderson MWPetersen GMde Andrade MCunningham JMWang YWu YMinna JChen QMandal DShu XOCoons TChow WHPinney SMZheng WSun ZGaba CKupert EBailey-Wilson JESchwartz AGYou MYang PGazdar AXiang YBGirard LfalseFine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.<h4>Purpose</h4>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).<h4>Experimental design</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.2009-01-01T00:00:00Z2009 Apr2024-11-13T06:42:41.736Z2019-03-27T00:25:04ZS-EPMC27460911935176310.1158/1078-0432.CCR-08-233510.1158/1078-0432.ccr-08-2335