To increase the power to discover prostate cancer susceptibility genes, the ICPCG, a multicenter collaborative research group (www.icpcg.org), increased sample size by combining genome-wide screen linkage data from 1233 prostate cancer families, and used dominant, recessive, and nonpara-metric models to analyze the data (63). Analysis of the complete family collection revealed "suggestive" evidence of linkage (logarithm of odds [LOD] > 1.86) at five regions: 5q12, 8p21, 15q11, 17q21, and 22q12; Table 1). The highest overall LOD score in the genome was 2.28 from the non-parametric analysis, found near marker D5S2858 on 5q12 (77 cM from pter). The linkage results by group for each of these five chromosomal regions are shown in Table 2. As seen in this table, with the exception of 17q21, the LOD scores for each of the highlighted regions are higher in the combined analysis than observed in any individual group, only reaching a level of "suggestive" evidence in the combined family data. This finding emphasizes the unique results that emerge from this combined approach.
Also performed were genome-wide screens in two subsets of families that may be enriched for stronger genetic effects. Among the 269 families with at least five affected members, "suggestive" evidence for linkage was found at 1q25, 8q13,13q14,16p13, and 17q21, and "significant" evidence of linkage (LOD = 3.57) was found at 22q12. LOD scores greater than 1.0 at 22q12 were observed in four different family collections. Among the 606 families with early age at diagnosis, "suggestive" evidence for linkage was found at 3p24,5q35,11q22, and Xq12 (Table 1).
To summarize this study:
1. No single major locus clearly emerged from this large study of prostate cancer families.
2. The finding of numerous "suggestive" linkages is consistent with the hypothesis of multiple prostate cancer susceptibility genes with modest effects, or several major genes segregating in small subsets of families.
3. The most significant evidence of linkage was observed in the subset of families with five or more affected members.
4. If major prostate cancer susceptibility genes exist, they are likely located in one or more of the regions implicated in this study.
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