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

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.

[1]  J. Carpten,et al.  Combined genome-wide scan for prostate cancer susceptibility genes. , 2004, Journal of the National Cancer Institute.

[2]  B. Karlan,et al.  Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  E. Ostrander,et al.  BRCA1 and BRCA2 Mutations in Women from Shanghai China , 2004, Cancer Epidemiology Biomarkers & Prevention.

[4]  E. Gillanders,et al.  Genome‐wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1 , 2003, The Prostate.

[5]  A. Whittemore,et al.  Where are the prostate cancer genes?—A summary of eight genome wide searches , 2003, The Prostate.

[6]  D. Jewell,et al.  Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31 , 2003, Gut.

[7]  Douglas F Easton,et al.  Cancer Incidence in BRCA1 mutation carriers. , 2002, Journal of the National Cancer Institute.

[8]  W. Foulkes,et al.  Founder BRCA1 and BRCA2 mutations in early‐onset French Canadian breast cancer cases unselected for family history , 2001, International journal of cancer.

[9]  A. Brothman,et al.  A common deletion at chromosomal region 17q21 in sporadic prostate tumors distal to BRCA1. , 2001, Genomics.

[10]  J. Stanford,et al.  Genetics of prostate cancer: too many loci, too few genes. , 2000, American journal of human genetics.

[11]  Jaana M. Hartikainen,et al.  Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland , 2000, European Journal of Human Genetics.

[12]  M. Stratton,et al.  The frequency of germ-line mutations in the breast cancer predisposition genes BRCA1 and BRCA2 in familial prostate cancer. The Cancer Research Campaign/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators. , 2000, Cancer research.

[13]  D J Schaid,et al.  Evidence for a prostate cancer-susceptibility locus on chromosome 20. , 2000, American journal of human genetics.

[14]  A. Jakubowska,et al.  Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. , 2000, American journal of human genetics.

[15]  D. Schaid,et al.  BRCA1 and BRCA2 have a limited role in familial prostate cancer. , 2000, Cancer research.

[16]  P. Oefner,et al.  Denaturing high-performance liquid chromatography detects reliably BRCA1 and BRCA2 mutations. , 1999, Genomics.

[17]  M. Rubin,et al.  Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men , 1999, The Prostate.

[18]  Jianfeng Xu,et al.  No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer , 1999, The Prostate.

[19]  E. Goode,et al.  Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. , 1999, American journal of human genetics.

[20]  Wen-Hwa Lee,et al.  Functional Domains of the BRCA1 and BRCA2 Proteins , 1998, Journal of Mammary Gland Biology and Neoplasia.

[21]  F. Collins,et al.  Evidence for a prostate cancer susceptibility locus on the X chromosome. , 1998, Nature Genetics.

[22]  W. Vogel,et al.  Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. , 1998, American journal of human genetics.

[23]  D A Meyers,et al.  Major Susceptibility Locus for Prostate Cancer on Chromosome 1 Suggested by a Genome-Wide Search , 1996, Science.

[24]  J. D. Thompson,et al.  Germ-line BRCA1 mutations in selected men with prostate cancer. , 1996, American journal of human genetics.

[25]  D. Grignon,et al.  Loss of heterozygosity of the BRCA1 and other loci on chromosome 17q in human prostate cancer. , 1995, Cancer research.

[26]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[27]  T. Beaty,et al.  Hereditary prostate cancer: epidemiologic and clinical features. , 1993, The Journal of urology.

[28]  M. King,et al.  Linkage of early-onset familial breast cancer to chromosome 17q21. , 1990, Science.

[29]  L. Lanzerotti Where Are the , 2006 .

[30]  O. Olopade,et al.  Breast cancer genetics in African Americans , 2003, Cancer.