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.

Segregation analysis of 1,546 prostate cancer families in Finland shows recessive inheritance

“…The International Consortium for Prostate Cancer Genetics (ICPCG), which seeks to improve the mapping of PCa genes, has emphasized that one of the major difficulties in studying PCa is genetic heterogeneity, possibly due to multiple, incompletely penetrant PCasusceptibility genes . Indeed using parametric (dominant and recessive) and nonparametric analyses on 1,233 families, Xu et al (2005) identified five distinct chromosomal regions with "suggestive" linkage (LOD score >1.86) to PCa, namely 5q12, 8p21, 15q11, 17q21, and 22q12. Subsets of the analyzed group of families characterized by large numbers of early-onset (≤65 years) PCa, which are more likely to segregate highly penetrant mutations, provided stronger evidence of linkage in several regions (including the 22q12 locus, with a LOD score of 3.57).…”

Familial testicular cancer: Interest in genetic testing among high-risk family members

“…In this regard, FTC may more closely resemble familial prostate cancer where there is a demonstrated interest in genetic testing, [17][18][19][20] with numerous candidate susceptibility loci having been identified, but to date no major susceptibility genes have been discovered to account for the majority of familial cases. 21 Thus, it is likely to take longer than anticipated to identify an FTC susceptibility gene and acquire the ability to perform germline mutation testing than it did with Hereditary Breast Ovarian Cancer (HBOC) or Hereditary Non Polyposis Colorectal Cancer (HNPCC). Even if a susceptibility gene were discovered tomorrow, it would probably take six months or more to get a clinical test to market; thus, our question about interest in a hypothetical genetic test was framed in a six-month context.…”

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease

“…1 Familial aggregation of the disease indicates that it has a genetic component. 2,3 Evidence presented by the International Consortium for Prostate Cancer Genetics (ICPCG) 4 highlighted five suggestive linkage regions supporting putative susceptibility loci reported earlier, including one on chromosome 5q. 5 More recently, several genome-wide association studies (GWAS) in large independent casecontrol data sets have provided compelling evidence for multiple new susceptibility loci.…”