Abstract 1854: In search of the founder haplotype on 7q11-21 in 18 Jewish prostate cancer families from the PROGRESS study
Authors: Karyadi Danielle M. , Karlins Eric , Wells Rick , Hung Hau , McIntosh Laura , Nelson Peter S. , Stanford Janet L. , Ostrander Elaine A. 
Published: February 2011

Abstract
Previously, a combined genome-wide linkage analysis of 36 Jewish prostate cancer (PC) families from the PROGRESS study and Johns Hopkins University identified a region of significant linkage on chromosome 7q11-21. Since the families are all from a single founder population, we hypothesized that the susceptibility mutation is most likely surrounded by a founder haplotype, which would occur more frequently in chromosomes shared by affected men versus other chromosomes in the families.
In order to develop a genetic map that was informative enough to identify the founder haplotype, 4852 SNPs were genotyped within the 77.2 Mb three recombination region on chromosome 7. Haplotypes shared amongst all affecteds within a family are termed “case haplotypes” while the remaining haplotypes segregating in each familiy are the “control haplotypes.” We identified haplotype patterns larger than 400 kb that are found more frequently among the case haplotypes compared to the control set. Multiple haplotypes have p-values less than 0.01, but only one region spans several overlapping hits. Although this region only contains 17 RefSeq genes, the area is duplicated several times making identification of the causal variant challenging.
We analyzed the region for copy number variations (CNVs) that could theoretically segregate with PC in these families as the long duplicated segment is known to promote large insertions and deletions within the region of interest. To do this, we designed a custom NimbleGen CGH array to cover 2.35 Mb that spanned the entire at-risk haplotype plus an additional 1.55 Mb. No duplication or deletion greater than 100 bp was found to segregate with the PC-associated haplotype.
Direct sequencing of the haplotype is challenging due to the multiple duplicate copies in the genome. All of the nonduplicated exons within the PC associated haplotype were sequenced. Of the duplicated exons, we were able to sequence 44 out of 60 using mismatched primers. Thus far, no polymorphism has been identified which segregates only with the at-risk haplotype. We recognize that the susceptibility mutation might affect enhancers or repressors and we are currently sequencing the nonduplicated areas, both upstream and downstream, of genes in the region.
Once the susceptibility mutation is identified, we will screen for the mutation in the remaining 18 Hopkins families that participated in the initial linkage study, as well as the remaining 289 PROGRESS families. We will look for the mutation to segregate with disease in these families as a statistical confirmation of the result. If the mutation proves difficult to identify, we will analyze the PC associated haplotype in these same families to confirm it is likely to be the founder haplotype surrounding the mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1854.