Truncating BRCA1 Mutations Are Uncommon in a Cohort of Hereditary Prostate Cancer Families with Evidence of Linkage to 17q Markers

Abstract

Purpose: A genome-wide scan of 175 hereditary prostate cancer families from the University of Michigan Prostate Cancer Genetics Project provided evidence of prostate cancer linkage to 17q markers near the BRCA1 gene. To examine the possibility that germ-line BRCA1 mutations were associated with hereditary prostate cancer, individuals from 93 families with evidence of linkage to chromosome 17q were screened for germ-line BRCA1 mutations.Experimental Design: One individual from each of the 93 families, the majority with three or more cases of prostate cancer, were screened for BRCA1 mutations with denaturing high-performance liquid chromatography (HPLC). Fragments exhibiting denaturing HPLC variant patterns were additionally analyzed by direct sequencing.Results: Sixty-five of the individuals selected for sequencing from 65 unrelated families were determined to have wild-type BRCA1 sequence by denaturing HPLC. One individual from a family with both prostate and ovarian cancer was found to have a truncating BRCA1 mutation (3829delT). An additional 27 germ-line variants were identified, including 15 missense variants.Conclusions: These sequencing results suggest that BRCA1 truncating mutations do not account for the linkage evidence on chromosome 17 observed in University of Michigan Prostate Cancer Genetics Project families. A recently completed combined genome scan has also detected linkage to 17q22, and studies are ongoing to identify the relevant prostate cancer susceptibility gene in this region.

Common Variation in the BRCA1 Gene and Prostate Cancer Risk

“…However, based on the HapMap CEU sample (January 2006 release), Gln 356 Arg does not show evidence of strong LD (R 2 z 0.5) with any known SNP on chromosome 17. Additionally, sequence analysis of the 93 unrelated men with prostate cancer from our previous screening study (8) indicates that Gln 356 Arg is not in LD (R 2 < 0.07) with any coding SNP in the BRCA1 gene (data not shown). Our other two associated SNPs, rs3737559 and rs799923, are located in noncoding sequences with no obvious functional effect and, based on the HapMap CEU sample, have a pair-wise R 2 of z0.5 with only 3 and 11 other known SNPs, respectively, on chromosome 17, none of which are located in coding or known regulatory regions.…”

“…Screening of hereditary prostate cancer families [including our own (8)], however, suggests that these rare, highly penetrant mutations are unlikely to account for a sizable fraction of hereditary prostate cancer cases (9)(10)(11). Still, to our knowledge, no large comprehensive study has definitively assessed the role of other sequence variations in BRCA1 (e.g., missense mutations) as a contributor to prostate cancer risk.…”

Signal transducer and activator of transcription 5A/B in prostate and breast cancers

“…Chromosome 17q showed allelic imbalance in prostate cancer (Latil et al 1994, Bova & Isaacs 1996, Alers et al 2000, Kasahara et al 2002, Wolter et al 2002a,b, Verhage et al 2003, von Knobloch et al 2004, and gains in chromosome 17q were detected in five studies (Bova & Isaacs 1996, Alers et al 2000, Kasahara et al 2002, Wolter et al 2002a. Moreover, three large studies linked a prostate cancer susceptibility gene to chromosome 17q (17q22) (Lange et al 2003, Gillanders et al 2004, Zuhlke et al 2004, suggesting involvement of genes in this region in an inherited form of prostate cancer.…”

Absence of truncating BRIP1 mutations in chromosome 17q-linked hereditary prostate cancer families

“…BRIP1 is B20 cM downstream from BRCA1 and both are contained near or within our linkage signal. Previous research from our laboratory failed to identify deleterious BRCA1 truncating mutations in chromosome 17-linked families (Zuhlke et al, 2004). In this study, we examine the role of germline BRIP1 variation in hereditary PCa, focusing on families with linkage evidence to 17q markers.…”