Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.

TitleFine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.
Publication TypeJournal Article
Year of Publication2009
AuthorsYou, M, Wang, D, Liu, P, Vikis, H, James, M, Lu, Y, Wang, Y, Wang, M, Chen, Q, Jia, D, Liu, Y, Wen, W, Yang, P, Sun, Z, Pinney, SM, Zheng, W, Shu, X-O, Long, J, Gao, Y-T, Xiang, Y-B, Chow, W-H, Rothman, N, Petersen, GM, de Andrade, M, Wu, Y, Cunningham, JM, Wiest, JS, Fain, PR, Schwartz, AG, Girard, L, Gazdar, A, Gaba, C, Rothschild, H, Mandal, D, Coons, T, Lee, J, Kupert, E, Seminara, D, Minna, J, Bailey-Wilson, JE, Amos, CI, Anderson, MW
JournalClin Cancer Res
Volume15
Issue8
Pagination2666-74
Date Published2009 Apr 15
ISSN1078-0432
KeywordsAged, Animals, Cell Line, Tumor, Chromosome Mapping, Chromosomes, Human, Pair 6, Female, Gene Knockdown Techniques, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Lung, Lung Neoplasms, Male, Mice, Mice, Nude, Microsatellite Repeats, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, RGS Proteins, RNA, Small Interfering, Transplantation, Heterologous
Abstract

PURPOSE: 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).EXPERIMENTAL DESIGN: 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.RESULTS: 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.CONCLUSION: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.

DOI10.1158/1078-0432.CCR-08-2335
Alternate JournalClin. Cancer Res.
PubMed ID19351763
PubMed Central IDPMC2746091
Grant ListR01 CA063700 / CA / NCI NIH HHS / United States
R01ES012063 / ES / NIEHS NIH HHS / United States
DE-FGB-95ER62060 / DE / NIDCR NIH HHS / United States
R01CA058554 / CA / NCI NIH HHS / United States
R01 ES013340 / ES / NIEHS NIH HHS / United States
R01CA63700 / CA / NCI NIH HHS / United States
P50 CA070907-03S29001 / CA / NCI NIH HHS / United States
R01 CA093643 / CA / NCI NIH HHS / United States
P50CA70907 / CA / NCI NIH HHS / United States
U01 CA076293 / CA / NCI NIH HHS / United States
R01 CA080127 / CA / NCI NIH HHS / United States
R01CA099187 / CA / NCI NIH HHS / United States
R01 CA058554 / CA / NCI NIH HHS / United States
P30CA22453 / CA / NCI NIH HHS / United States
/ / Intramural NIH HHS / United States
P30 ES006096 / ES / NIEHS NIH HHS / United States
R01CA099147 / CA / NCI NIH HHS / United States
R01CA80127 / CA / NCI NIH HHS / United States
P30ES06096 / ES / NIEHS NIH HHS / United States
R01 CA099147 / CA / NCI NIH HHS / United States
P30 CA015083 / CA / NCI NIH HHS / United States
U01 CA076293-09 / CA / NCI NIH HHS / United States
R01CA093643 / CA / NCI NIH HHS / United States
P30 CA022453 / CA / NCI NIH HHS / United States
P30CA 15083 / CA / NCI NIH HHS / United States
P50 CA070907 / CA / NCI NIH HHS / United States
N01PC35145 / CA / NCI NIH HHS / United States
R01 CA099187 / CA / NCI NIH HHS / United States
R01ES013340 / ES / NIEHS NIH HHS / United States
R01 ES012063 / ES / NIEHS NIH HHS / United States
U01CA76293 / CA / NCI NIH HHS / United States
N01HG65404 / HG / NHGRI NIH HHS / United States
N01-PC35145 / PC / NCI NIH HHS / United States
R03 CA077118 / CA / NCI NIH HHS / United States