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Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease
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Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease
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Journal Article
Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease
2009
Overview
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.
Publisher
Springer International Publishing,Nature Publishing Group
Subject
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Chromosomes, Human, Pair 5 - genetics
/ Disease
/ DNA
/ Family
/ Fundamental and applied biological sciences. Psychology
/ General aspects. Genetic counseling
/ Genes
/ Genetic Predisposition to Disease - genetics
/ Genetics
/ Genetics of eukaryotes. Biological and molecular evolution
/ Genomes
/ Genotype
/ Humans
/ Male
/ Molecular and cellular biology
/ Nephrology. Urinary tract diseases
/ Pedigree
/ Prostate
/ Prostatic Neoplasms - genetics
/ Single-nucleotide polymorphism
/ Tumors
