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J Pathol. 2012 May;227(1):29-41. doi: 10.1002/path.4003. Epub 2012 Feb 23.

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers.

Author information

The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
Signal Transduction Laboratory, Cancer Research UK London Research Institute, WC2A 3LY, UK.
Institut Curie, INSERM U830, 75248 Paris, France.
Breakthrough Research Unit, Bermondsey Wing, Guy's Hospital, London, SE1 9RT, UK.
CRUK Clinical Trials Unit, The Institute of Cancer Research, Sutton, SM2 5NG, UK.
University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
Institut Curie, Department of Tumour Biology, 75248 Paris, France.
Signal Transduction Team, Division of Cell and Molecular Biology, The Institute of Cancer Research, London, SW3 6JB, UK.
Centre for Cancer Research and Cell Biology, Queen's University, Belfast, BT9 7BL, Northern Ireland, UK.
Nuclear Receptor Transcription Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, CB2 0RE, UK.
Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham and Nottingham University Hospitals Trust, Nottingham, NG7 2UH, UK.
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, WC2A 3LY, UK.
UCL Cancer Institute, Huntley Street, London WC1E 6DD, UK.
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, H2W 1S6, Canada.
Contributed equally


BRCA1 encodes a tumour suppressor protein that plays pivotal roles in homologous recombination (HR) DNA repair, cell-cycle checkpoints, and transcriptional regulation. BRCA1 germline mutations confer a high risk of early-onset breast and ovarian cancer. In more than 80% of cases, tumours arising in BRCA1 germline mutation carriers are oestrogen receptor (ER)-negative; however, up to 15% are ER-positive. It has been suggested that BRCA1 ER-positive breast cancers constitute sporadic cancers arising in the context of a BRCA1 germline mutation rather than being causally related to BRCA1 loss-of-function. Whole-genome massively parallel sequencing of ER-positive and ER-negative BRCA1 breast cancers, and their respective germline DNAs, was used to characterize the genetic landscape of BRCA1 cancers at base-pair resolution. Only BRCA1 germline mutations, somatic loss of the wild-type allele, and TP53 somatic mutations were recurrently found in the index cases. BRCA1 breast cancers displayed a mutational signature consistent with that caused by lack of HR DNA repair in both ER-positive and ER-negative cases. Sequencing analysis of independent cohorts of hereditary BRCA1 and sporadic non-BRCA1 breast cancers for the presence of recurrent pathogenic mutations and/or homozygous deletions found in the index cases revealed that DAPK3, TMEM135, KIAA1797, PDE4D, and GATA4 are potential additional drivers of breast cancers. This study demonstrates that BRCA1 pathogenic germline mutations coupled with somatic loss of the wild-type allele are not sufficient for hereditary breast cancers to display an ER-negative phenotype, and has led to the identification of three potential novel breast cancer genes (ie DAPK3, TMEM135, and GATA4).

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