Description of the international consortium for prostate cancer genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13

Daniel J. Schaid, Bao Li Chang

The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility.