A Genome Screen of Multiplex Sibships with Prostate Cancer

Abstract

Analysis of a genome screen of 504 brothers with prostate cancer (CaP) who were from 230 multiplex sibships identified five regions with nominally positive linkage signals, on chromosomes 2q, 12p, 15q, 16p, and 16q. The strongest signal in these data is found on chromosome 16q, between markers D16S515 and D16S3040, a region suspected to contain a tumor-suppressor gene. On the basis of findings from previous genome screens of families with CaP, three preplanned subanalyses were carried out, in the hope of increasing the subgroup homogeneity. Subgroups were formed by dividing the sibships into a group with a positive family history (FH+) that met criteria for "hereditary" CaP (n=111) versus those which did not meet the criteria (n=119) and by dividing the families into those with a mean onset age below the median (n=115) versus those with a mean onset age above the median (n=115). A separate subanalysis was carried out for families with a history of breast cancer (CaB+ [n=53]). Analyses of these subgroups revealed a number of potentially important differences in regions that were nonsignificant when all the families were analyzed together. In particular, the subgroup without a positive family history (FH-) had a signal in a region that is proximal to the putative site of the HPC1 locus on chromosome 1, whereas the late-age-at-onset group had a signal on 4q. The CaB+ subgroup revealed a strong linkage signal at 1p35.1.

Germline mutations in E‐cadherin do not explain association of hereditary prostate cancer, gastric cancer and breast cancer

“…21 In addition, in genome wide scans with prostate cancer families, positive LOD scores have been reported at 16q. 22 The aim of this study is to see if germline mutations in CDH1 can explain the association of gastric and /or breast cancers in HPC families. In addition 3 hereditary prostate cancer (HGC) families from northern Sweden were also screened for germline mutations in the CDH1 gene.…”

A missense substitution A49T in the steroid 5-alpha-reductase gene (SRD5A2) is not associated with prostate cancer in Finland

“…Recently, several loci have been implied in predisposing to prostate cancer by genetic linkage studies in cancer families. These include the HPC-1 locus at 1q24-q25 (Smith et al, 1996), HPC2 at 1q42-q43 (Berthon et al, 1998), HPCX at Xq27-q28 (Xu et al, 1998), HPBC at 1p36 (Gibbs et al, 1999), and loci at 20q13 (Berry et al, 2000), 11p (Gibbs et al, 2000) and 16q (Suarez et al, 2000). Exploration of the genetic basis of prostate cancer susceptibility by linkage analysis is challenging due to genetic heterogeneity (the large number of loci involved), due to incomplete penetrance of germline mutations and due to clustering of sporadic prostate cancer.…”

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

“…Many different studies consistently report PrCa as highly heritable. 5,[7][8][9][10] At least 15 different loci have been linked to hereditary PrCa (HPC) through linkage analysis in highly aggregated families. So far, a few genes have been positively identified in the search for high-penetrance PrCa susceptibility loci, but the evidence does not suggest that risk alleles in these genes explain large proportions of either HPC or nonhereditary PrCa because the risk alleles at this loci appear to be quite rare.…”