Validation of prostate cancer risk-related loci identified from genome-wide association studies using family-based association analysis: evidence from the International Consortium for Prostate Cancer Genetics (ICPCG)

Abstract

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case–control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case–control GWAS are also associated with disease risk in HPC families.

Identification of functionally active, low frequency copy number variants at 15q21.3 and 12q21.31 associated with prostate cancer risk

“…rate is comparable to other recent studies (15,16) and could be attributed to cohort and disease heterogeneity (17,18).…”

The 2013 Genetics Society of America Medal

“…Half of Elaine's laboratory has focused on the genetics of human cancer, particularly prostate cancer, which involves large international collaborations to conduct and validate GWAS results (Kote-Jarai et al 2011;Jin et al 2012;Lu et al 2012). While the biomedical relevance of this work is extremely high (17% of American men will get prostate cancer), the genetics are proving to be somewhat more difficult than trait mapping in dogs.…”

“…While the biomedical relevance of this work is extremely high (17% of American men will get prostate cancer), the genetics are proving to be somewhat more difficult than trait mapping in dogs. However, recent studies have successfully identified candidate loci associated with susceptibility to prostate cancer in high-risk families and certain populations (Jin et al 2012;Stott-Miller et al 2012;Taioli et al 2012;Xu et al 2013).…”

Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

“…Genome-wide association studies have identified more than 75 common alleles that are also associated with increased PC risk, and although many of these have been validated, each is predicted to make a small contribution to disease risk 19–25. Finally, family-based association studies have contributed additional validated loci 26,27…”