Prostate Cancer Susceptibility Locus on Chromosome 1q: A Confirmatory Study

Abstract

Background: Recent recognition that a predisposition to prostate cancer can be inherited has led to a search for specific genes associated with the disease. Through a study of families with three or more affected first-degree relatives, a region on the long arm of chromosome 1 (i.e., 1q24-25) has been tentatively identified as containing a gene, HPC1, involved in the development of hereditary prostate cancer. Confirmation of this finding is needed, however, before attempts are made to isolate and characterize the putative HPC1 gene. Purpose: To confirm that chromosome 1q24-25 contains a gene relevant to hereditary prostate cancer, we analyzed an independent set of families, each with two or more affected individuals. Methods: Fifty-nine unrelated families were selected for analysis on the sole criterion that more than one living family member was affected by prostate cancer. DNA samples were subsequently isolated from 130 individuals with the disease. These samples were genotyped at six polymorphic marker sequences (D1S215, D1S2883, D1S466, D1S158, D1S518, and D1S2757) covering the chromosomal region proposed to contain HPC1. The resulting data were analyzed by nonparametric multipoint linkage (NPL) methods, yielding NPL Z scores and corresponding one-sided P values. Results: When the entire set of 59 families was considered, the occurrence of prostate cancer (and, presumably, the HPC1 gene) was most tightly linked to marker D1S466 (NPL Z score = 1.58; P = .0574). Analysis of the 20 families (51 affected individuals) fulfilling one or more of the proposed clinical criteria for hereditary prostate cancer (i.e., three or more affected individuals within one nuclear family; affected individuals in three successive generations [maternal or paternal lineage]; and/or clustering of two or more individuals affected before the age of 55 years) revealed more convincing evidence of disease linkage to chromosome 1q24-25 (maximum NPL Z score [at marker D1S466] = 1.72; P = .0451). The 39 families (79 affected individuals) that did not meet the clinical criteria for hereditary prostate cancer exhibited no significant evidence of dis-*Affiliations of authors:

Genetic risk and behavioural change

“…13-15 These advances enable appropriate detection and risk management strategies to be implemented years before cancer develops, with the potential to reduce mortality. 16 17 However, in order for such testing to reduce risk and mortality, people who are at risk must change their behaviour.…”

RNASEL mutations in hereditary prostate cancer

“…Fifty-nine families from the PCGP were used in the first confirmatory report of prostate cancer linkage to chromosome 1q24-25 markers. 4 In this present report, we set out to determine the contribution of RNASEL mutations to prostate cancer susceptibility in a set of PCGP families.…”

No evidence of germline PTEN mutations in familial prostate cancer

“…One prostate cancer susceptibility locus ( HPC1 ) has been reported on 1q24-253 and confirmed by Cooney et al 4 and Gronberg et al 5 Latest estimates suggest that this locus would only account for 4% of families overall in the UK (upper 95% confidence interval (CI) limit of 31%) 6. Another locus has been reported on 1q42.2-43 after a genome wide search of 47 French and German families 7.…”