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Open Access Research article

Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry

Letitia D Smith1, Andrea A Tesoriero12, Ee M Wong1, Susan J Ramus3, Frances P O'Malley45, Anna Marie Mulligan56, Mary Beth Terry7, Ruby T Senie7, Regina M Santella8, Esther M John9, Irene L Andrulis1045, Hilmi Ozcelik5, Mary B Daly11, Andrew K Godwin1117, Saundra S Buys12, Stephen Fox13, David E Goldgar14, Graham G Giles15, John L Hopper16 and Melissa C Southey1*

Author Affiliations

1 Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia

2 QIAGEN Pty. Ltd., Doncaster, Victoria 3108, Australia

3 Gynaecological Cancer Research Laboratory, Institute for Women's Health, University College London, 74 Huntley Street, London, WC1E 6AU, UK

4 Department of Pathology and Laboratory Medicine, Mt Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada

5 Department of Pathobiology and Laboratory Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada

6 St Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada

7 Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, USA

8 Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 722 West 168th Street, New York, NY 10032, USA

9 Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Fremont, CA 94538, USA

10 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Molecular Genetics, University of Toronto, Ontario Cancer Genetics Network, Cancer Care Ontario, 620 University Avenue, Toronto, ON, M5G 2C1, Canada

11 Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA

12 Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA

13 Department of Pathology, Peter MacCallum Cancer Center, St Andrew's Place, East Melbourne, Victoria 3002, Australia

14 Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA

15 Cancer Epidemiology Centre, The Cancer Council Victoria, Rathdowne Street, Carlton 3052, Australia

16 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria 3010, Australia

17 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA

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Breast Cancer Research 2011, 13:R14  doi:10.1186/bcr2822

Published: 31 January 2011

Abstract

Introduction

Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1.

Methods

We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification.

Results

Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively.

Conclusions

Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations.