A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics

Abstract

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Figure 1

Combined genomewide screen for PC-susceptibility genes with use of nonparametric and parametric multipoint linkage analyses among the entire set of 1,233 PC-affected families recruited from 10 ICPCG members. LOD scores obtained from parametric analysis with use of a dominant model (blue line), a recessive model (red line), and nonparametric analysis (yellow line) are plotted by individual chromosome for the whole genome.

Figure 2

Combined genomewide screen for PC-susceptibility genes with use of nonparametric and parametric multipoint linkage analyses among 269 families with at least five affected members recruited from 10 ICPCG members. LOD scores obtained from parametric analysis with use of a dominant model (blue line), a recessive model (red line), and nonparametric analysis (yellow line) are plotted by individual chromosome for the whole genome.

Figure 3

Parametric linkage analysis of chromosome 22 among families with at least five affected members with use of the dominant model. LOD scores are plotted for each of the 10 ICPCG groups.

Figure 4

Combined genomewide screen for PC-susceptibility genes with use of nonparametric and parametric multipoint linkage analyses among 606 families with family mean age at diagnosis ⩽65 years recruited from 10 ICPCG members. LOD scores obtained from parametric analysis with use of a dominant model (blue line), a recessive model (red line), and nonparametric analysis (yellow line) are plotted by individual chromosome for the whole genome.