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Previous genome-wide association studies (GWAS) of prostate cancer risk focused on cases unselected for family history and have reported over 100 significant associations. The International Consortium for Prostate Cancer Genetics (ICPCG) has now performed a GWAS of 2511 (unrelated) familial prostate cancer cases and 1382 unaffected controls from 12 member sites. All samples were genotyped on the Illumina 5M+exome single nucleotide polymorphism (SNP) platform. The GWAS identified a significant evidence for association for SNPs in six regions previously associated with prostate cancer in population-based cohorts, including 3q26.2, 6q25.3, 8q24.21, 10q11.23, 11q13.3, and 17q12. Of note, SNP rs138042437 (p = 1.7e(-8)) at 8q24.21 achieved a large estimated effect size in this cohort (odds ratio = 13.3). 116 previously sampled affected relatives of 62 risk-allele carriers from the GWAS cohort were genotyped for this SNP, identifying 78 additional affected carriers in 62 pedigrees. A test for an excess number of affected carriers among relatives exhibited strong evidence for co-segregation of the variant with disease (p = 8.5e(-11)). The majority (92 %) of risk-allele carriers at rs138042437 had a consistent estimated haplotype spanning approximately 100 kb of 8q24.21 that contained the minor alleles of three rare SNPs (dosage minor allele frequencies <1.7 %), rs183373024 (PRNCR1), previously associated SNP rs188140481, and rs138042437 (CASC19). Strong evidence for co-segregation of a SNP on the haplotype further characterizes the haplotype as a prostate cancer predisposition locus.

Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p ≤ 1E (-3)) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may contribute risk to aggressive disease.

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.

Multiple prostate cancer (PCa) risk-related loci have been discovered by genome-wide association studies (GWAS) based on case-control designs. However, GWAS findings may be confounded by population stratification if cases and controls are inadvertently drawn from different genetic backgrounds. In addition, since these loci were identified in cases with predominantly sporadic disease, little is known about their relationships with hereditary prostate cancer (HPC). The association between seventeen reported PCa susceptibility loci was evaluated with a family-based association test using 1,979 hereditary PCa families of European descent collected by members of the International Consortium for Prostate Cancer Genetics, with a total of 5,730 affected men. The risk alleles for 8 of the 17 loci were significantly over-transmitted from parents to affected offspring, including SNPs residing in 8q24 (regions 1, 2 and 3), 10q11, 11q13, 17q12 (region 1), 17q24 and Xp11. In subgroup analyses, three loci, at 8q24 (regions 1 and 2) plus 17q12, were significantly over-transmitted in hereditary PCa families with five or more affected members, while loci at 3p12, 8q24 (region 2), 11q13, 17q12 (region 1), 17q24 and Xp11 were significantly over-transmitted in HPC families with an average age of diagnosis at 65 years or less. Our results indicate that at least a subset of PCa risk-related loci identified by case-control GWAS are also associated with disease risk in HPC families.

Prostate cancer (PCa) is the most frequently diagnosed cancer in men worldwide and is likely to be caused by a number of genes with different modes of inheritance, population frequencies and penetrance. The objective of this study was to assess the familial aggregation of PCa in a sample of 1,546 nuclear families ascertained through an affected father and diagnosed during 1988-1993, from the unique, founder population-based resource of the Finnish Cancer Registry. Segregation analysis was performed for two cohorts of 557 early-onset and 989 late-onset families evaluating residual paternal effects and assuming that age at diagnosis followed a logistic distribution after log-transformation. The results did not support an autosomal dominant inheritance as has been reported in many of the hospital-based prostatectomy series. Instead, it confirmed the existence of hereditary PCa in the Finnish population under a complex model that included a major susceptibility locus with Mendelian recessive inheritance and a significant paternal regressive coefficient that is indicative of a polygenic/multifactorial component. The strengths of our study are the homogenous Finnish population, large epidemiological population-based data, histologically confirmed cancer diagnosis done before the PSA-era in Finland and registry based approach. Our results support the evidence that the inheritance of PCa is controlled by major genes and are in line with the previous linkage studies. Moreover, this is the first time a recessive inheritance is suggested to fit PCa in all data even when divided to early and late-onset cohorts.

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.

Prostate cancer represents a significant worldwide public health burden. Epidemiological and genetic epidemiological studies have consistently provided data supporting the existence of inherited prostate cancer susceptibility genes. Segregation analyses of prostate cancer suggest that a multigene model may best explain familial clustering of this disease. Therefore, modeling gene-gene interactions in linkage analysis may improve the power to detect chromosomal regions harboring these disease susceptibility genes. In this study, we systematically screened for prostate cancer linkage by modeling two-locus gene-gene interactions for all possible pairs of loci across the genome in 426 prostate cancer families from Johns Hopkins Hospital, University of Michigan, University of Umeå, and University of Tampere. We found suggestive evidence for an epistatic interaction for six sets of loci (target chromosome-wide/reference marker-specific P< or =0.0001). Evidence for these interactions was found in two independent subsets from within the 426 families. While the validity of these results requires confirmation from independent studies and the identification of the specific genes underlying this linkage evidence, our approach of systematically assessing gene-gene interactions across the entire genome represents a promising alternative approach for gene identification for prostate cancer.

Background: Prostate cancer (PRCA) is the most common cancer in males in the western world. In Finland PRCA has an age-adjusted incidence of 81.5 per 100,000. We previously reported that in Finland, the late-onset cases in families with "no-male-to-male" (NMM) transmission of PRCA accounted for most of the linkage to the HPCX region (Xq27-28). The aim of the present study was to test for linkage disequilibrium (LD) and haplotype-sharing around marker DXS1205 between cases from hereditary prostate cancer (HPC) families and population controls. The initial allelic association was performed between 108 PRCA cases and 257 population controls genotyped for 23 markers in the Xq26-28 region. This resulted in a highly significant nominal one-sided Fisher's exact P-value of 0.0003 for allele ''180'' of marker DXS1205. Subsequently, a similar level of significance was observed for the same allele for marker DXS1205 (P=0.0002) when comparing 60 NMM cases and 257 controls. These results were still significant after Bonferroni correction for multiple testing. Fine mapping efforts included the genotyping of four additional markers D3S2390, bG82i1.9, bG82i1.1, bG82i1.0 and four single nucleotide polymorphisms (SNPs) to augment the original markers around DXS1205., Results: Our major finding is that markers extending from ''D3S2390'' to ''bG82i1.0'' flank the critical locus, about 150 kb. Levin and Bertell's LD measure (delta), a guide to localization of a possible variant, was 0.42 and 0.41 for alleles of markers bG82i1.9 and DXS1205, respectively., Conclusions: In this study, the most significant haplotype comprised the three tightly linked, contiguous markers: ''cen-bG82i1.9-SNP-Hap B-bG82i1.1-tel'' [''197-2-234''] among several possible haplotypes (nominal Fisher's one-sided P=0.003). The two transcription units mapping within this interval are the LDOC1 and SPANXC genes. Positional cloning of the HPCX gene(s) is being facilitated by this exploration of the Xq26-28 region. This study represents the first report identifying a haplotype in the Xq27-28 region for an association between HPCX and X-linked prostate cancer with no-male-to-male transmission in the Finnish population.

In a recent genome-wide linkage (GWL) analysis of Finnish families at high risk for prostate cancer, we found two novel putative susceptibility loci at 3p25-p26 and 11q14. Here, we report the fine-mapping of these two critical regions at high resolution with 39 microsatellite markers in 16 families, including multiplex families that were not used in the GWL scan. The maximum multipoint HLOD was 3.39 at 3p26 and 1.42 at 11q14. The highest LOD scores were seen around markers D3S1270 and D3S4559 (alpha=0.89), covering approximately two megabases. The two known genes in this region CHL1 (cell adhesion molecule with homology to L1CAM) and CNTN6 (contactin 6) were screened for exonic mutations in the families showing the strongest linkage, but no disease-segregating sequence variants were observed. The recombination map pointed to a region proximal to the area of best linkage, suggesting that more genes may need to be investigated as candidates. These results provide strong evidence for the existence of a prostate cancer susceptibility gene at 3p26 in Finnish prostate cancer families. This locus has not been strongly linked with hereditary prostate cancer in other populations. However, the mildly positive 3p LOD scores in a recent GWL analysis of patients from the United States suggest that the locus may also be important in other populations.

Recent studies have suggested that polymorphisms of the androgen receptor gene ( AR) may influence the risk of prostate cancer (PC) development and progression. Here, we analyzed the length of the CAG repeat of the AR gene in 1363 individuals, including patients with PC, benign prostate hyperplasia (BPH), and population controls. There was a tendency for short CAG repeats to be associated with PC. The Odds Ratio (OR) for PC was 1.47 ( P=0.05) when individuals with short CAG repeats (18). CAG repeat length was not significantly associated with family history, disease stage, grade, age at diagnosis, prostate-specific antigen (PSA) level at diagnosis, or prognosis of the patients. Unexpectedly, short CAG repeats were significantly less common in patients with BPH compared with controls (OR=0.47, P=0.03). Our results suggest that the CAG polymorphism of the AR gene is unlikely to have a major role in the development or progression of PC in the Finnish population. The association of CAG repeats with the risk of BPH warrants further study.

Salla disease is a lysosomal storage disorder due to impaired transport of free sialic acid across the lysosomal membrane. The clinical presentation of this autosomal recessive trait is severe psychomotor retardation from early infancy on. In order to determine the gene locus for the disease we have initiated a genetic linkage study using polymorphic gene markers in representative family material comprising about 60% of all families known to be affected with Salla disease. Here we present an exclusion map based on combined linkage data from 64 informative loci on 19 autosomes. Theoretically, at least 55% of the genome has been excluded as a locus for the disease gene, while some chromosome areas, particularly the long arm of chromosome 2, are highlighted as possible sites for the gene locus.

Salla disease is an inherited lysosomal storage disorder caused by accumulation of free sialic acid in the lysosomes. Lamp genes, lamp A and lamp B (lysosome associated membrane proteins), are the first known genes encoding for human lysosomal membrane proteins. Absence of linkage in a large group of families shows that lamp genes are not involved in Salla disease. The lamp genes were localized, using Southern hybridization in hamster--human hybrid cell panels, to chromosomes 13 (lamp A) and X (lamp B).