Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families

Abstract

Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.

Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.

Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.

Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.

Figure 1

Multipoint HLODs using the GWS marker set and the two-liability class parametric model: a) using all families, b) in the subset of families with 2–3 affected males and possible male-to-male transmission of prostate cancer, c) in the subset of families that were not included in the original HPCX linkage paper [3,38] with 2–3 affected males and possible male-to-male transmission of prostate cancer, d) in the subset of families with 2–3 affected males that also meet the Carter criteria, e) in the subset of families with 2–3 affected males that also meet the Carter criteria and were not included in the original HPCX linkage paper [38]. Panel f is from the UCSC Genome Browser ( http://genome.ucsc.edu) on the Human February 2009 (GRCh37/hg19) Assembly of the human genome and shows the 2-LOD drop linkage interval from the HLOD graph in panel c. This region extends from approximately 122 cM to 144 cM, bounded by markers GATA165B12 and DXS1232, spanning base pair positions 120877968 to 139280361.

Figure 2

Pedigree that exhibits both potential male-to-male transmission and potential maternal inheritance of prostate cancer. In this family, with a maximum LOD of 1.7 in the HPCX region, all five maternally related affected males share a linked haplotype (shaded black) in this region and the one paternally-related affected male does not share this haplotype. The numbers in the shapes are liability classes based on affection status and age.