© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
Combined Genome-Wide Scan for Prostate Cancer Susceptibility Genes
Affiliations of authors: National Human Genome Research Institute, National Institutes of Health, Bethesda, MD (EMG, JEBW, ABB, MPJ, DG, ER, JA); Center for Human Genomics (JX, BC, LZ, DAM) and Department of Public Health (EML, WMB), Wake Forest University School of Medicine, Winston-Salem, NC; Department of Radiation Sciences, Oncology, University of Umeå, Umeå, Sweden (FW, HG); Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA (ABB); Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD (SDI, KEW, PCW, WBI); Departments of Internal Medicine (CEM) and Urology (KAC), University of Michigan, Ann Arbor, MI; Department of Urology (MPM, TLJT) and Institute of Medical Technology (AR, JS), University of Tampere and Tampere University Hospital, Tampere, Finland; Translational Genomics Research Institute (TGen), Phoenix, AZ (JD, JMT)
Correspondence to: Jianfeng Xu, MD, PhD, Medical Center Blvd., Winston-Salem, NC 27157 (e-mail: jxu{at}wfubmc.edu) or Jeffrey M. Trent, PhD, TGen, 400 N. Fifth St., Suite 1600, Phoenix, AZ 85004 (e-mail: jtrent{at}tgen.org)
Background: Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer. Methods: We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided. Results: The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P = .00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P<.00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P = .00008). Conclusion: Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted.
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