A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region

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Abstract
Background: Prostate cancer (PRCA) is the most common cancer in males in the western world. In Finland PRCA has an age-adjusted incidence of 81.5 per 100,000. We previously reported that in Finland, the late-onset cases in families with “no-male-to-male” (NMM) transmission of PRCA accounted for most of the linkage to the HPCX region (Xq27-28). The aim of the present study was to test for linkage disequilibrium (LD) and haplotype-sharing around marker DXS1205 between cases from hereditary prostate cancer (HPC) families and population controls. The initial allelic association was performed between 108 PRCA cases and 257 population controls genotyped for 23 markers in the Xq26-28 region. This resulted in a highly significant nominal one-sided Fisher’s exact P-value of 0.0003 for allele ″180″ of marker DXS1205. Subsequently, a similar level of significance was observed for the same allele for marker DXS1205 (P=0.0002) when comparing 60 NMM cases and 257 controls. These results were still significant after Bonferroni correction for multiple testing. Fine mapping efforts included the genotyping of four additional markers D3S2390, bG82i1.9, bG82i1.1, bG82i1.0 and four single nucleotide polymorphisms (SNPs) to augment the original markers around DXS1205. Results: Our major finding is that markers extending from ″D3S2390″ to ″bG82i1.0″ flank the critical locus, about 150 kb. Levin and Bertell’s LD measure (δ), a guide to localization of a possible variant, was 0.42 and 0.41 for alleles of markers bG82i1.9 and DXS1205, respectively. Conclusions: In this study, the most significant haplotype comprised the three tightly linked, contiguous markers: ″cen-bG82i1.9-SNP-Hap B-bG82i1.1-tel″ [″197-2-234″] among several possible haplotypes (nominal Fisher’s one-sided P=0.003). The two transcription units mapping within this interval are the LDOC1 and SPANXC genes. Positional cloning of the HPCX gene(s) is being facilitated by this exploration of the Xq26-28 region. This study represents the first report identifying a haplotype in the Xq27-28 region for an association between HPCX and X-linked prostate cancer with no-male-to-male transmission in the Finnish population.