Human Molecular Genetics Advance Access published online on January 17, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddm375
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SnoRNA U50 is a candidate tumor suppressor gene at 6q14.3 with a mutation associated with clinically significant prostate cancer
1 Winship Cancer Institute and Department of Hematology and Oncology, Emory University School of Medicine, 1365 Clifton Road, Atlanta, GA 30322, USA 2 Epidemiology and Surveillance Research Department, American Cancer Society, 1599 Clifton Road, Atlanta, GA 30329, USA 3 Program in Genetics and Molecular Biology 4 Department of Urology 5 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1365 Clifton Road, Atlanta, GA 30322, USA 6 Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Atlanta, GA 30033, USA 7 Department of Urology, University of Washington, Seattle, WA 98195, USA 8 Department of Surgery, Washington University School of Medicine, Barnes-Jewish Hospital, St. Louis, MO 63110, USA
* To whom correspondence should be addressed at: Jin-Tang Dong, Winship Cancer Institute, Emory University School of Medicine, 1365 Clifton Road, Room C4080, Atlanta, Georgia, USA. Tel: 404-712-2568; Fax: 404-712-2571; Email: jdong2{at}emory.edu
Received August 28, 2007; Revised November 29, 2007; Accepted December 19, 2007
Deletion of chromosome 6q14-q22 is common in multiple human cancers including prostate cancer, and chromosome 6 transferred into cancer cells induces senescence and reduces cell growth, tumorigenicity and metastasis, indicating the existence of one or more tumor suppressor genes in 6q. To identify the 6q tumor suppressor gene, we first narrowed the common region of deletion to a 2.5-Mb interval at 6q14-15. Of the 11 genes located in this minimal deletion region and expressed in normal prostates, only snoRNA U50 was mutated, demonstrated transcriptional downregulation, and inhibited colony formation in prostate cancer cells. The mutation, a homozygous 2-bp (TT) deletion, was found in 2 of 30 prostate cancer cell lines/xenografts and 9 of 89 localized prostate cancers (11 of 119 or 9% cancers). Two of 89 (2%) patients with prostate cancer also showed the same mutation in their germline DNA, but none of 104 cancer-free control men did. The homozygous deletion abolished U50 function in a colony formation assay. Analysis of 1371 prostate cancer cases and 1371 matched control men from a case-control study nested in a prospective cohort showed that, although a germline heterozygous genotype of the deletion was detected in both patients and controls at similar frequencies, the homozygosity of the deletion was significantly associated with clinically significant prostate cancer (odds ratio=2.9, 95% confidence interval=1.17 – 7.21). These findings establish snoRNA U50 as a reasonable candidate for the 6q tumor suppressor gene in prostate cancer and likely in other types of cancers.