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Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clin Cancer Res 2009 Apr 15;15(8):2666-74 PMID: 19351763 PMCID: PMC2746091

Pubmed ID

19351763

DOI

10.1158/1078-0432.CCR-08-2335

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.

Author List

You 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 XO, Long J, Gao YT, Xiang YB, Chow WH, 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

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Associate Professor in the Physiology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-65249131768   56 Citations

MESH terms used to index this publication - Major topics in bold

Aged
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
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e