Abstract 1341: Identification of significant linkage evidence for lethal prostate cancer on chromosome arm 11p15.

Abstract We performed genome wide linkage analysis in a set of high-risk prostate cancer pedigrees, each with 3 or more sampled cases whose death certificate indicated a contribution of prostate cancer to death (lethal prostate cancer). All prostate cancer cases were present in the Utah SEER Cancer Registry (pathology confirmed); all “lethal” prostate cancer cases were also required to have a Utah death certificate indicating prostate cancer as a contributing cause of death. A set of markers with no linkage disequilibrium was selected for linkage analysis. We took the intersection of SNP markers from five Illumina genotyping platforms used (550K, 610K, 1M,Omni_express (720k), and Omni_1M), resulting in selection of 301,646 markers. We began with the first marker on each chromosome and then skipped markers until one satisfied all criteria (min 0.1 cM distance, heterozygosity 0.35, R-squared < 0.16 -using HapMap's LD files based on CEPH). This resulted in selection of a set of 25,436 SNP LD-free genome wide markers for linkage. We have performed genome-wide linkage analysis for 21 of the genotyped high-risk lethal prostate cancer pedigrees with the 25,436 selected SNP markers. Genome wide hetLODs showed one significant linkage peak for the recessive model on chromosome 14 (LOD = 4.20). The pedigree with the highest LOD in this region has a +2.69; we are attempting to expand sampling for other pedigrees with linkage evidence in this region. A single pedigree with 16 prostate cancer cases, at least 4 of whom have already died from prostate cancer and were sampled, provided a LOD score = +3.56 on chromosome arm 11p15. An 11p15 haplotype inherited in common from the founder to 6 generations of descendants is shared in at least 9 of the prostate cancer cases, 3 of whom died from prostate cancer. The 1-LOD drop defined support interval for the pedigree linked to chromosome 11 occurs at approximately 34-46 cM and contains 13 currently documented genomic features, several of which may be reasonable candidates for lethal prostate cancer including the gene PRMT3 (arginine methyltransferase 3), DAL-1, NELL1, FANCF (Fanconi anemia, complementation group F), and GAS2 (growth arrest-specific 2). Sequencing of multiple haplotype sharing cases in the pedigree is underway. Citation Format: Lisa A. Cannon-Albright, Craig C. Teerlink, Neeraj Agarwal. Identification of significant linkage evidence for lethal prostate cancer on chromosome arm 11p15. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1341. doi:10.1158/1538-7445.AM2013-1341