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Haplotype and Cell Proliferation Analyses of Candidate Lung Cancer Susceptibility Genes on Chromosome 15q24-25.1

¹ Washington University, St. Louis, Missouri; ² National Human Genome Research Institute, Bethesda, Maryland; ³ M.D. Anderson Cancer Center, Houston, Texas; ⁴ University of Cincinnati, Cincinnati, Ohio; ⁵ Mayo Clinic College of Medicine, Rochester, Minnesota; ⁶ National Cancer Institute, Rockville, Maryland; ⁷ University of Colorado, Denver, Colorado; ⁸ Karmanos Cancer Institute, Detroit, Michigan; ⁹ University of Texas Southwestern Medical Center, Dallas, Texas; ¹⁰ University of Toledo College of Medicine, Toledo, Ohio; and ¹¹ Louisiana State University Health Science Center, New Orleans, Louisiana

Requests for reprints: Ming You, Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 Euclid Avenue, Box 8109, St. Louis, MO. Phone: 314-362-9294; Fax: 314-362-9366; E-mail: youm{at}wustl.edu.

Key Words: 15q24-25.1 • PSMA4 • lung cancer

Recent genome-wide association studies have linked the chromosome 15q24-25.1 locus to nicotine addiction and lung cancer susceptibility. To refine the 15q24-25.1 locus, we performed a haplotype-based association analysis of 194 familial lung cases and 219 cancer-free controls from the Genetic Epidemiology of Lung Cancer Consortium (GELCC) collection, and used proliferation and apoptosis analyses to determine which gene(s) in the 15q24-25.1 locus mediates effects on lung cancer cell growth in vitro. We identified two distinct subregions, hapL (P = 3.20 x 10^–6) and hapN (P = 1.51 x 10^–6), which were significantly associated with familial lung cancer. hapL encompasses IREB2, LOC123688, and PSMA4, and hapN encompasses the three nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3, and CHRNB4. Examination of the genes around hapL revealed that PSMA4 plays a role in promoting cancer cell proliferation. PSMA4 mRNA levels were increased in lung tumors compared with normal lung tissues. Down-regulation of PSMA4 expression decreased proteasome activity and induced apoptosis. Proteasome dysfunction leads to many diseases including cancer, and drugs that inhibit proteasome activity show promise as a form of cancer treatment. Genes around hapN were also investigated, but did not show any direct effect on lung cancer cell proliferation. We concluded that PSMA4 is a strong candidate mediator of lung cancer cell growth, and may directly affect lung cancer susceptibility through its modulation of cell proliferation and apoptosis. [Cancer Res 2009;69(19):7844–50]