1. ¹Genetics Unit, Menzies Research Institute, University of Tasmania, Hobart, Australia
2. ²Karolinska Institutet, KI-Alzheimer Disease Research Centre, Stockholm, Sweden
3. ³Department of Statistics, University of California, Berkeley, CA, USA
4. ⁴Histopathology Department, Royal Hobart Hospital, Hobart, Australia
5. ⁵Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia
6. ⁶Department of Ophthalmology, Royal Children's Hospital, Melbourne, Australia
7. ⁷Murdoch Children's Research Institute, Melbourne, Australia
8. ⁸CSIRO Preventative Health National Research Flagship, North Ryde, New South Wales, Australia
9. ⁹CSIRO Molecular and Health Technologies, North Ryde, New South Wales, Australia
10. ¹⁰Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
11. ¹¹International Agency for Research on Cancer, Lyon, France

Correspondence: Dr JL Dickinson, Menzies Research Institute, Private Bag 23, Hobart, Tasmania 7001, Australia. Tel: +61 3 62267622; Fax: +61 3 62267704; E-mail: jo.dickinson@utas.edu.au

Received 6 June 2008; Revised 25 July 2008; Accepted 29 August 2008; Published online 1 October 2008.

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.