Nature Genetics
8, 399 - 404 (1994)
doi:10.1038/ng1294-399
Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten familiesLori S. Friedman1, Elizabeth A. Ostermeyer1, Csilla I. Szabo1, Patrick Dowd1, Eric D. Lynch1, Sarah E. Rowell1
& Mary-Claire King1
1Department of Molecular & Cell Biology and School of Public Health, University of California, Berkeley, California 94720, USA We provide genetic evidence supporting the identity of the candidate gene for BRCA1 through the characterization of germline mutations in 63 breast cancer patients and 10 ovarian cancer patients in ten families with cancer linked to chromosome 17q21. Nine different mutations were detected by screening BRCA1 DNA and RNA by single-strand conformation polymorphism analysis and direct sequencing. Seven mutations lead to protein truncations at sites throughout the gene. One missense mutation (which occurred independently in two families) leads to loss of a cysteine in the zinc binding domain. An intronic single basepair substitution destroys an acceptor site and activates a cryptic splice site, leading to a 59 basepair insertion and chain termination. The four families wrth both breast and ovarian cancer had chain termination mutations in the N-terminal half of the protein.
REFERENCES
- Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66−71 (1994).
- Hall, J.M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684−1689 (1990).
- Albertsen, H.M. et al. A physical map and candidate genes in the BRCA1 region on chromosome 17q12−21. Nature Genet. 7, 472−479 (1994).
- Sharp, P.A. Split genes and RNA splicing. Cell 77, 805−815. (1994).
- Friedman, L.S. et al. The search for BRCA1 and the cloning of 22 genes from chromosome 17q21. Cancer Res. (in the press).
- American Society of Human Genetics. Statement on genetic testing for breast and ovarian cancer. Am. J. hum. Genet. 55, 860 (1994).
- Rowell, S., Newman, B., Boyd, J. & King, M-C. Inherited predisposition to breast and ovarian cancer. Am. J. hum. Genet. 55, 861−865 (1994).
- Arena, J.F. et al. Inherited breast cancer: Confirmation of linkage to BRCA2, possible linkage to the estrogen receptor, and the clinical implications of genetic complexity. J. Am. med. Assoc. (in the press).
|
