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Somatic and Germline Mutations of the BRCA2 Gene in Sporadic Ovarian Cancer¹

Cancer Research Campaign Human Cancer Genetics Research Group, Box 238, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ [K. A. F., P. H., P. R., B. A. J. P., S. A. G.], United Kingdom; The Queensland Institute of Medical Research, 300 Herston Road, Brisbane, QLD 4006, Australia [J. K., G. C-T.]; Department of Gynecological Oncology Research, The Roswell Park Cancer Institute, 5709 Simpson Building, Elm and Carlton Streets, Buffalo, New York 14263 [R. A. D.]; Department of Obstetrics and Gynaecology, Derby City General Hospital, Uttoxeter Road, Derby DE22 3NE [I. V. S.], United Kingdom; and Ovarian Cancer Screening Unit, The Royal Hospitals National Health Service Trust, St. Bartholomew's Hospital, West Smithfield, London EC1A 7BE [I. J.], United Kingdom

The breast and ovarian cancer susceptibility gene BRCA2 has recently been isolated. A role for BRCA2 in sporadic breast and ovarian cancer has been suggested by loss of heterozygosity (LOH) studies which show frequent LOH in the BRCA2 region at chromosome 13q12. In addition, the observation of nonrandom loss of the wild-type chromosome in a breast/ovarian cancer family which shows linkage to BRCA2 suggests it may act as a tumor suppressor gene. To determine the extent of somatic alteration involving BRCA2 in sporadic ovarian cancer, 50 tumors were analyzed for mutations throughout the entire BRCA2 coding region. Mutations predicted to result in truncation of the BRCA2 protein were detected in four tumors. Analysis of germline DNA revealed two of these alterations to be of somatic origin. In addition, all four tumors exhibited loss of the second BRCA2 allele as predicted by Knudson's hypothesis for a tumor suppressor gene. These results suggest that, as is the case with BRCA1, somatic mutations of BRCA2 are infrequent in sporadic ovarian cancer, despite the relatively high frequency of LOH detected around the BRCA2 locus.

¹ The laboratory work in this study was funded by a program grant from the CRC, the Queensland Cancer Fund, the National Health and Medical Research Council, Core Grant CA16056 of the National Cancer Institute, and the Gustavus and Louise Pfeiffer Foundation (R. A. D.). K. F. was supported by the Overseas Research Student Award Scheme and the National Science Foundation Graduate Fellowship Program. B. A. J. P. is a Gibb Fellow of the CRC. I. J. is a McElwain Fellow of the CRC. G. C-T is a National Health and Medical Research Council Research Fellow.

² To whom requests for reprints should be addressed. Fax: 44 1223 336902.

Received 4/22/96. Accepted 7/ 1/96.

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