Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease

FitzGerald, LM; Patterson, B; Thomson, R; Polanowski, A; Quinn, S; Brohede, J; Thornton, T; Challis, D; Mackey, DA; Dwyer, T; Foote, S; Hannan, GN; Stankovich, J; Mckay, JD; Dickinson, JL

Author(s): FitzGerald, LM; Patterson, B; Thomson, R; Polanowski, A; Quinn, S; Brohede, J; Thornton, T; Challis, D; Mackey, DA; Dwyer, T; Foote, S; Hannan, GN; Stankovich, J; Mckay, JD; Dickinson, JL;
Details: Publication Year 2009-03,Volume 17,Issue #3,Page 368-377
Journal Title: EUROPEAN JOURNAL OF HUMAN GENETICS
Publication Type: Journal Article
Abstract: Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14Mb haplotype on chromosome 5 (5p13-q12) inherited identical-by-descent (IBD) by multiple cases. Microsatellite genotyping of additional deceased case samples confirmed that a total of eight cases inherited the common haplotype (P = 0.0017). Re-sequencing of eight prioritised candidate genes in the region in six selected individuals identified 15 SNPs segregating with the IBD haplotype, located within the ITGA2 gene. Three of these polymorphisms were selected for genotyping in an independent Tasmanian data set comprising 127 cases with familial prostate cancer, 412 sporadic cases and 319 unaffected controls. Two were associated with prostate cancer risk: rs3212649 (OR 1.67 (1.07-2.6), P = 0.0009) and rs1126643 (OR 1.52 (1.01-2.28), P = 0.0088). Significant association was observed in both familial and sporadic prostate cancer. Although the functional SNP remains to be identified, considerable circumstantial evidence, provided by in vivo and in vitro studies, supports a role for ITGA2 in tumour development.
Publisher: NATURE PUBLISHING GROUP
Keywords: GENOME-WIDE ASSOCIATION; COMMON SEQUENCE VARIANTS; LINKAGE ANALYSIS; DIFFERENTIAL EXPRESSION; DOMINANT INHERITANCE; NEOPLASTIC PROSTATE; COMPLEX TRAITS; ALPHA(2) GENE; POLYMORPHISMS; SCAN
Publisher's Version: https://doi.org/10.1038/ejhg.2008.171
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2009-03-01 12:00:00