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

Departments of ¹ Internal Medicine, ² Urology, and ³ Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan; ⁴ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan; ⁵ Clinical Research and Human Biology Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington; and ⁶ Department of Public Health Sciences, Section on Biostatistics, Wake Forest School of Medicine, Winston-Salem, North Carolina

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.

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