title: Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.
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 14 Mb 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.
authors.affiliation: Genetics Unit, Menzies Research Institute, University of Tasmania, Hobart, Australia.
authors.forename: Liesel M
authors.initials: LM
authors.lastname: FitzGerald
authors.forename: Briony
authors.initials: B
authors.lastname: Patterson
authors.forename: Russell
authors.initials: R
authors.lastname: Thomson
authors.forename: Andrea
authors.initials: A
authors.lastname: Polanowski
authors.forename: Stephen
authors.initials: S
authors.lastname: Quinn
authors.forename: Jesper
authors.initials: J
authors.lastname: Brohede
authors.forename: Timothy
authors.initials: T
authors.lastname: Thornton
authors.forename: David
authors.initials: D
authors.lastname: Challis
authors.forename: David A
authors.initials: DA
authors.lastname: Mackey
authors.forename: Terence
authors.initials: T
authors.lastname: Dwyer
authors.forename: Simon
authors.initials: S
authors.lastname: Foote
authors.forename: Garry N
authors.initials: GN
authors.lastname: Hannan
authors.forename: James
authors.initials: J
authors.lastname: Stankovich
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Dickinson
mesh_terms: D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D005190:Family; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D010375:Pedigree; D011471:Prostatic Neoplasms / Q000235:genetics*; D012307:Risk Factors