Human Molecular Genetics, Vol 4, 1811-1817, Copyright © 1995 by Oxford University Press
CI Szabo and MC King
An estimated 5 to 10% of all breast and ovarian cancer is attributable to
inherited mutations in two highly penetrant autosomal dominant
susceptibility genes, BRCA1 and BRCA2. BRCA1 confers higher risk of ovarian
cancer and BRCA2 much higher risk of male breast cancer. With the exception
of missense mutations in the RING finger near the amino terminus of BRCA1,
virtually all germline mutations in the gene cause the novel BRCA1 protein
to be prematurely truncated. Approximately 90% of breast tumors in BRCA1
families, 50% of unselected breast tumors and 65-80% of unselected ovarian
tumors have lost one allele of BRCA1 by somatic deletion. Very few tumors
have detectable somatic point mutations in BRCA1. Inhibition of BRCA1
expression in mammary epithelial cell lines also suggests that BRCA1 may
act as a tumor suppressor. The biological function of BRCA1 is still
unknown, although identification of a patient homozygous for an inherited
BRCA1 mutation suggests that the gene's function may be essential only to
specific tissues. At least two other genes, P53 and the androgen receptor,
are responsible for inherited predisposition to breast cancer in rare
families. Several epidemiologic studies suggest that individuals carrying
rare alleles at a minisatellite flanking the HRAS locus are at increased
risk of cancer, including breast cancer. Finally, preliminary epidemiologic
studies also suggest that individuals heterozygous for mutations in the
ataxia telangiectasia gene may be at increased risk of breast cancer.
REVIEWS
Inherited breast and ovarian cancer
Department of Medicine, University of Washington, Seattle, USA.
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