DCEG has coordinated multiple genome-wide association studies (GWAS) of prostate cancer. Each of these efforts is described below.
The prostate cancer genome-wide association study (GWAS) included genotyping approximately 550,000 single nucleotide polymorphisms (SNPs) in 1,172 prostate cancer patients and 1,157 controls of European ancestry from the Prostate, Lung, Colon and Ovarian (PLCO) study. The original analysis published in Nature Genetics (see below) included 2,282 subjects. After improvement and revisions of the original analysis, 2,252 subjects were submitted to dbGaP.
In stage 2, investigators tested 26,958 SNPs in four independent studies (total of 3,941 cases and 3,964 controls). In the combined joint analysis, they confirmed three previously reported loci (two independent SNPs at 8q24 and one in HNF1B (formerly known as TCF2 on 17q); P < 10-10). In addition, loci on chromosomes 7, 10 (two loci) and 11 were highly significant (between P < 7.31 x 10-13 and P < 2.14 x 10-6). Loci on chromosome 10 include MSMB, which encodes β-microseminoprotein, a primary constituent of semen and a proposed prostate cancer biomarker, and CTBP2, a gene with antiapoptotic activity; the locus on chromosome 7 is at JAZF1, a transcriptional repressor that is fused by chromosome translocation to SUZ12 in endometrial cancer. Of the nine loci that showed highly suggestive associations (P < 2.5 x 10-5), four best fit a recessive model and included candidate susceptibility genes: CPNE3, IL16 and CDH13. Our findings point to multiple loci with moderate effects associated with susceptibility to prostate cancer that, taken together, in the future may predict high risk in select individuals.
Yeager M et al. Genome-Wide Association Study of Prostate Cancer Identifies a Second Locus at 8q24. Nat Genet 2007.
Thomas G et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 2008.
Most men diagnosed with prostate cancer will experience indolent disease; hence, discovering genetic variants that distinguish aggressive from nonaggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, investigators identified two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49 × 10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18 × 10-8). In a stratified case-control analysis, the single nucleotide polymorphism at 5q14.3 appears specific for aggressive prostate cancer (P=8.85 × 10-5) with no association for nonaggressive prostate cancer compared with controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
Berndt SI et al. Two susceptibility loci identified for prostate cancer aggressiveness. Nat Commun 2015.
Participants were recruited through the Ghana Prostate Study—with both clinical and population-based components yielding 500 cases and 500 controls.