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

Ming You, Daolong Wang, Pengyuan Liu, Haris Vikis, Michael James, Yan Lu, Yian Wang, Min Wang, Qiong Chen, Dongmei Jia, Yan Liu, Weidong Wen, Ping Yang, Zhifu Sun, Susan M. Pinney, Wei Zheng, Xiao Ou Shu, Jirong Long, Yu Tang Gao, Yong Bing XiangWong Ho Chow, Nat Rothman, Gloria M. Petersen, Mariza De Andrade, Yanhong Wu, Julie M. Cunningham, Jonathan S. Wiest, Pamela R. Fain, Ann G. Schwartz, Luc Girard, Adi Gazdar, Colette Gaba, Henry Rothschild, Diptasri Mandal, Teresa Coons, Juwon Lee, Elena Kupert, Daniela Seminara, John Minna, Joan E. Bailey-Wilson, Christopher I. Amos, Marshall W. Anderson

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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 ofLung 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 ofmatched 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.

Original languageEnglish (US)
Pages (from-to)2666-2674
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number8
DOIs
StatePublished - Apr 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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