Statistical recombinant mapping in extended high-risk Utah pedigrees narrows the 8q24 prostate cancer locus to 2.0 Mb

Chromosome 8q24 is a region of compelling interest for prostate cancer (PRCA). Linkage, association, and admixture analysis initially indicated the region. Subsequently, several variants at 8q24 have been found to independently associate with PRCA. One compelling hypothesis is allelic heterogeneity, whereby multiple variants affect the regulation of the same gene. In addition to potential allelic heterogeneity, 8q24 exhibits strong linkage disequilibrium over vast distances and is prone to chromosomal aberrations.

Allelic heterogeneity and complex chromosomal structure are factors that hinder progress towards gene identification using association. Linkage techniques, however, are robust to allelic heterogeneity and therefore can contribute important localization information. We have used a linkage-based localization technique to perform recombinant mapping in eight high-risk Utah pedigrees.

Using pedigree-based recombinant mapping we identify a 5.7 Mb region at 8q24.21-22, between markers D8S1774 and D8S557. Considering our region with the localization previously presented, we can delimit the 8q24 PRCA locus to a 2.0 Mb consensus interval from 127.5 to 129.5 Mb.

We have used a linkage-based, recombinant mapping technique in extended high-risk Utah pedigrees to successfully narrow the 8q24 PRCA locus. The region we present halves the 95% credible interval previously described using admixture analysis and contains only three annotated genes: FAM84B, MYC, and TMEM75. It should be noted that LD stretches far beyond the interval we describe, and hence this region adds important information about where to focus future efforts to isolate the causal variants and underlying gene, whether by linkage or association techniques.