![]() ![]() ![]() One approach is to study a much larger number of families, which should improve the statistical power to detect regions containing genes that are mutated in a small proportion of families. These difficulties are inherent to PC-linkage studies, and, although they cannot be completely overcome, several approaches can be used to reduce their impact. ![]() PC linkage may be further complicated by phenocopies, particularly given the high prevalence of the disease and widespread use of prostate-specific antigen screening. Briefly, it is likely that multiple genes predispose to PC and that no single gene is sufficiently important to provide a reliable linkage signal when a small number of families are analyzed. The difficulties in mapping PC genes have been widely discussed (Isaacs and Xu 2002 Edwards and Eeles 2004 Ostrander et al. 2002).ĭespite these extensive efforts, linkage findings suggested by individual groups and proposed associations with variants in candidate genes have not been reproducibly replicated by other groups. Furthermore, several genes in regions linked to PC have been proposed as candidate HPC genes, notably ELAC2 (MIM 605367), RNASEL (MIM 180435), and MSR1 (MIM 153622) (Tavtigian et al. 2003), and numerous regions have been suggested as harboring hereditary PC (HPC) genes. More than a dozen genomewide screens have been performed (Easton et al. Research groups worldwide have recruited families with multiple members with PC and have performed linkage analyses to search for PC-susceptibility genes. Segregation analyses and twin studies strongly suggest that genetic factors explain at least some of the familial aggregation of PC (reviewed by Schaid ). 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.įamilial clustering of prostate cancer (PC ) has been consistently recognized for many years (reviewed by Isaacs and Xu ). In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of ⩽65 years. 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. 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. 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. One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. 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 of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. Cannon-Albright, 11 and Daniela Seminara 12, *Įvidence of the existence of major prostate cancer (PC)–susceptibility genes has been provided by multiple segregation analyses. Hoegel, 9 Walther Vogel, 9 Thomas Paiss, 9 Fredrik Wiklund, 10 Monica Emanuelsson, 10 Elisabeth Stenman, 10 Björn-Anders Jonsson, 10 Henrik Grönberg, 10 Nicola J. Matikainen, 8 Teuvo LJ Tammela, 8 Joan Bailey-Wilson, 8 Johanna Schleutker, 8 Christiane Maier, 9 Kathleen Herkommer, 9 Josef J. Cooney, 7 Tarja Ikonen, 8 Agnes Baffoe-Bonnie, 8 Henna Fredriksson, 8 Mika P. Jarvik, 6 Marta Janer, 6 Leroy Hood, 6 Elaine A. Friedrichsen, 6 Kerry Deutsch, 6 Suzanne Kolb, 6 Michael Badzioch, 2,6 Gail P. Balise, 3 Ingrid Oakley-Girvan, 3 Alice S. Hopper, 2 Lovise Mahle, 2 Pal Moller, 2 Tim Bishop, 2 Chris Evans, 2 Steve Edwards, 2 Julia Meitz, 2 Sarah Bullock, 2 Questa Hope, 2 ACTANE Consortium, 2 Chih-lin Hsieh, 3 Jerry Halpern, 3 Raymond N. Jianfeng Xu, 1 Latchezar Dimitrov, 1 Bao-Li Chang, 1 Tamara S. ![]()
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