Prostate Cancer, Hereditary, 6

For a general discussion of hereditary prostate cancer, see 176807.

Xu et al. (2005) performed genomewide linkage analysis in 269 prostate cancer families with at least 5 affected members and found significant linkage at chromosome 22q12 (lod score, 3.57).

Camp et al. (2006) noted that at least 8 other studies had pointed to chromosome 22q12.3 as a site of particular significance in prostate cancer, with lod scores ranging from 1.50 to 3.57. They performed fine mapping and localization of the region using a pedigree-specific recombinant mapping approach in 14 informative, high-risk Utah pedigrees. These 14 pedigrees were chosen because they were either 'linked' or 'haplotype-sharing' pedigrees or both. 'Linked' pedigrees were those with significant pedigree-specific linkage evidence pointing to the 22q12.3 region, regardless of the number of prostate cancer cases sharing the segregating haplotype. 'Haplotype-sharing' pedigrees were those with at least 5 prostate cancer cases sharing a segregating haplotype in the 22q12.3 region, regardless of the linkage evidence. Using this approach, Camp et al. (2006) identified a segment at 22q12.3 between markers D22S1265 and D22S277 as the region most likely to contain the 22q prostate cancer predisposition gene. To further refine the linkage of prostate cancer to chromosome 22q12.3, Camp et al. (2007) added 40 new pedigrees with prostate cancer to the 14 Utah kindreds from their previous study. When all 54 pedigrees were considered, the consensus region was narrowed to a 2.2-Mb region flanked by D22S281 and D22S683, which included 11 genes.

Johanneson et al. (2008) performed fine mapping using haplotype and recombination data from 42 high-risk families and found that no clear consensus interval was present when all families were used. However, in a subset of 14 families with 5 or more affected men per family, they identified a 2.53-Mb shared consensus segment overlapping the previously published interval; combining their results with earlier data reduced the critical region at chromosome 22q12.3 to approximately 1.36 Mb.

Johanneson et al. (2010) performed family-based association testing using SNPs in the 22q12 region to reevaluate the 42 families with prostate cancer from 2 independent cohorts identified by Johanneson et al. (2008). There were 150 men with prostate cancer with available DNA. Compared to 506 unrelated Caucasian controls, the strongest association was found with 2 SNPS: rs2097465 and rs2017329 (p values of both about 7.0 x 10(-5)) at the 5-prime end of the APOL3 (607253) gene. Sequencing of the APOL3 gene identified an upstream SNP (rs132660) that also showed an association. The findings refined the candidate region to 15 kb. An association with rs132660 was confirmed in another data set of 1,320 patients and 1,266 controls; however, in an additional sample of 1,176 cases and 1,105 controls, there was no association with rs132660 or rs2097465.