HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG).

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

Pooled genome linkage scan of aggressive prostate cancer: results from the International Consortium for Prostate Cancer Genetics.

While it is widely appreciated that prostate cancers vary substantially in their propensity to progress to a life-threatening stage, the molecular events responsible for this progression have not been identified. Understanding these molecular mechanisms could provide important prognostic information relevant to more effective clinical management of this heterogeneous cancer. Hence, through genetic linkage analyses, we examined the hypothesis that the tendency to develop aggressive prostate cancer may have an important genetic component. Starting with 1,233 familial prostate cancer families with genome scan data available from the International Consortium for Prostate Cancer Genetics, we selected those that had at least three members with the phenotype of clinically aggressive prostate cancer, as defined by either high tumor grade and/or stage, resulting in 166 pedigrees (13%). Genome-wide linkage data were then pooled to perform a combined linkage analysis for these families. Linkage signals reaching a suggestive level of significance were found on chromosomes 6p22.3 (LOD = 3.0), 11q14.1-14.3 (LOD = 2.4), and 20p11.21-q11.21 (LOD = 2.5). For chromosome 11, stronger evidence of linkage (LOD = 3.3) was observed among pedigrees with an average at diagnosis of 65 years or younger. Other chromosomes that showed evidence for heterogeneity in linkage across strata were chromosome 7, with the strongest linkage signal among pedigrees without male-to-male disease transmission (7q21.11, LOD = 4.1), and chromosome 21, with the strongest linkage signal among pedigrees that had African American ancestry (21q22.13-22.3; LOD = 3.2). Our findings suggest several regions that may contain genes which, when mutated, predispose men to develop a more aggressive prostate cancer phenotype. This provides a basis for attempts to identify these genes, with potential clinical utility for men with aggressive prostate cancer and their relatives.

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

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.

Results of a genome-wide linkage analysis in prostate cancer families ascertained through the ACTANE consortium.

BACKGROUND: The aggregation of prostate cancer within families suggests a major inherited component to the disease. Genetic linkage studies have identified several chromosomal regions that may contain prostate cancer susceptibility loci, but none has been definitively implicated. METHODS: We performed a genome-wide linkage search based on 64 families, 63 with at least 3 cases of prostate cancer, ascertained in five countries. The majority of cases from these centers presented with clinically detected disease. Four hundred and one polymorphic markers were typed in 268 individuals. Multipoint heterogeneity analysis was conducted under three models of susceptibility; non-parametric analyses were also performed. RESULTS: Some weak evidence of linkage, under at least one of the genetic models, was observed to markers on chromosomes 2 (heterogeneity LOD (HLOD) = 1.15, P = 0.021), 3 (HLOD = 1.25, P = 0.016), 4 (HLOD = 1.28, P = 0.015), 5 (HLOD = 1.20, P = 0.019), 6 (HLOD = 1.41, P = 0.011), and 11 (HLOD = 1.24, P = 0.018), and in two regions on chromosome 18 (HLOD = 1.40, P = 0.011 and HLOD = 1.34, P = 0.013). There were no HLOD scores greater than 1.5 under any model, and no locus would be predicted to explain more than half of the genetic effect. No evidence in favor of linkage to previously suggested regions on chromosomes 1, 8, 17, 20, or X was found. CONCLUSIONS: Genetic susceptibility to prostate cancer is likely to be controlled by many loci, with no single gene explaining a large fraction of the familial risk. Pooling of results from all available genome scans is likely to be required to obtain definitive linkage results.