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Genetic Linkage of Prostate Cancer Risk to the Chromosome 3 Region Bearing FHIT

¹ Divisions of Molecular Medicine and ² Information Sciences, Beckman Research Institute and ³ Department of Cancer Genetics, City of Hope National Medical Center, Duarte, California; ⁴ Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, California; ⁵ Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts; ⁶ Department of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania; ⁷ Department of Medicine, Division of Hematology/Oncology and ⁸ Clinical Research Office, Robert J. Lurie Comprehensive Cancer Center, Northwestern University School of Medicine, Chicago, Illinois; ⁹ Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; ¹⁰ Department of Medicine, Hematology-Oncology Division, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania; ¹¹ Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida; ¹² University of Wisconsin Comprehensive Cancer Center and University of Wisconsin School of Medicine, Madison, Wisconsin; ¹³ Division of Hematology & Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee; ¹⁴ Barbara Ann Karmanos Cancer Institute, Detroit, Michigan; and ¹⁵ Department of Epidemiology and Biostatistics, Case Western Reserve University, Metro Health Medical Center, Cleveland, Ohio

Requests for reprints: Theodore G. Krontiris, Division of Molecular Medicine, Beckman Research Institute, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000. Phone: 626-359-8111 ext. 64297; Fax: 626-930-5394; E-mail: tkrontir{at}.coh.org.

We conducted linkage analysis of 80 candidate genes in 201 brother pairs affected with prostatic adenocarcinoma. Markers representing two adjacent candidate genes on chromosome 3p, CDC25A and FHIT, showed suggestive evidence for linkage with single-point identity-by-descent allele-sharing statistics. Fine-structure multipoint linkage analysis yielded a maximum LOD score of 3.17 (P = 0.00007) at D3S1234 within FHIT intron 5. For a subgroup of 38 families in which three or more affected brothers were reported, the LOD score was 3.83 (P = 0.00001). Further analysis reported herein suggested a recessive mode of inheritance. Association testing of 16 single nucleotide polymorphisms (SNP) spanning a 381-kb interval surrounding D3S1234 in 202 cases of European descent with 143 matched, unrelated controls revealed significant evidence for association between case status and the A allele of single nucleotide polymorphism rs760317, located within intron 5 of FHIT (Pearson's ² = 8.54, df = 1, P = 0.0035). Our results strongly suggest involvement of germline variations of FHIT in prostate cancer risk.

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