Germline BRCA1–2 Mutations in Non-Ashkenazi Families with Double Primary Breast and Ovarian Cancer 1 John O. Schorge, M.D., 2 Neda M. Mahoney, M.D., David S. Miller, M.D., Robert L. Coleman, M.D., Carolyn Y. Muller, M.D., David M. Euhus, M.D., and Gail E. Tomlinson, M.D., Ph.D. Harold C. Simmons Comprehensive Cancer Center and Familial Cancer Registry, Departments of Obstetrics and Gynecology, Department of Pediatrics, and Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593 Received June 5, 2001 Objective. Ashkenazi women with double primary breast and ovarian cancerhave a high prevalence (57%) of germline Jewish founder mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes. The purpose of this study was to de- termine the frequency and type of BRCA1–2 mutations in non- Ashkenazi families with at least one member having double pri- mary breast and ovarian cancer. Methods. Women at increased risk for cancer based upon their family history were enrolled at the University of Texas Southwest- ern Familial Cancer Registry between 1992 and 2000. Blood sam- ples from patients desiring genetic testing were sent for complete DNA sequencing of the BRCA1 and BRCA2 genes. Families with a member having both breast and ovarian cancer were identified and clinical data were obtained. Results. Sixty-two (7%) of 900 enrolled families were non-Ash- kenazi and had at least one member with double primary breast and ovarian cancer. Twenty-one families had members who un- derwent genetic testing;41 did not. Thirteen (62%) families had a germline BRCA1 (n  11) or BRCA2 (n  2) mutation; only one Jewish founder mutation (185delAG) was detected. Eight (38%) families tested negative. Six (86%) of seven women undergoing genetic testing who themselves had double primary breast and ovarian cancer were BRCA1–2 mutation carriers. Conclusions. Germline BRCA1–2 mutations are common in non-Ashkenazi families with a member having double primary breast and ovarian cancer. These mutations occurred throughout both genes, emphasizing the need for comprehensive sequencing. One family had the BRCA2 6985delCT mutation, which lies be- yond the “ovarian cancer cluster” region. © 2001 Academic Press Key Words: BRCA1–2 mutations; double primary malignancy; ovarian cancer; breast cancer. INTRODUCTION Ashkenazi women with double primary tumors in the breast and ovary have a high prevalence (57%) of germline Jewish founder mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes [1]. However, Ashkenazi women who develop only ovarian cancer are also frequent carriers of a founder mutation [2– 4]. Hundreds of separate BRCA1–2 mutations that predispose to the development of breast and ovarian cancer have been reported in non-Ashkenazi women [5– 8]. Some of these mutations are known to be recurring mutations in various ethnic groups [8 –12]. In the United States, the majority of women are of non- Ashkenazi descent. Genetic testing of high-risk patients having familial breast and ovarian cancer often identifies unique mu- tations [6, 13]. For this reason, non-Ashkenazi women with family histories suggestive of an inherited syndrome for de- veloping breast and ovarian cancer warrant comprehensive sequencing of BRCA1 and BRCA2. BRCA1–2 mutations are twice as common among breast cancer families having an individual with a second non-breast type of primary cancer [14]. In a mathematical model, Berry et al. reported that a woman having both breast and ovarian cancer has a probability of carrying a mutation in excess of 80%, even with no other information about family history [15]. The purpose of this study was to determine the frequency and type of BRCA1 and BRCA2 mutations in non-Ashkenazi fam- ilies having a member with double primary breast and ovarian cancer. MATERIALS AND METHODS Familial Cancer Registry The University of Texas Southwestern Familial Cancer Reg- istry was established in 1992 to identify and monitor people who have an increased risk of cancer due to their family background. Participants have generally been made aware of the project through media coverage or referred for consultation 1 This study was supported by NIH CA RO3-CA70472 (GT), the Susan Komen Breast Cancer Foundation (GT), and the Mary Brown Breast Cancer Risk Assessment Center (DE, GT). 2 To whom correspondence and reprint requests should be addressed at Division of Gynecologic Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., J7.124, Dallas, TX 75390-9032. Fax: (214) 648-8404. E-mail: John.Schorge@UTSouthwestern.edu. Gynecologic Oncology 83, 383–387 (2001) doi:10.1006/gyno.2001.6431, available online at http://www.idealibrary.com on 383 0090-8258/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.