title: A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers.
abstract: 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).
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Maryou B
authors.initials: MB
authors.lastname: Lambros
authors.affiliation: Signal Transduction Laboratory, Cancer Research UK London Research Institute, WC2A 3LY, UK.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wilkerson
authors.affiliation: Institut Curie, INSERM U830, 75248 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Manie
authors.affiliation: Breakthrough Research Unit, Bermondsey Wing, Guy's Hospital, London, SE1 9RT, UK.
authors.forename: Anita
authors.initials: A
authors.lastname: Grigoriadis
authors.affiliation: CRUK Clinical Trials Unit, The Institute of Cancer Research, Sutton, SM2 5NG, UK.
authors.forename: Roger
authors.initials: R
authors.lastname: A'Hern
authors.affiliation: University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: van der Groep
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.affiliation: Institut Curie, INSERM U830, 75248 Paris, France.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Popova
authors.affiliation: Institut Curie, Department of Tumour Biology, 75248 Paris, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Mariani
authors.affiliation: Signal Transduction Team, Division of Cell and Molecular Biology, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Samra
authors.initials: S
authors.lastname: Turaljic
authors.affiliation: Signal Transduction Team, Division of Cell and Molecular Biology, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Furney
authors.affiliation: Signal Transduction Team, Division of Cell and Molecular Biology, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Daniel-Nava
authors.initials: DN
authors.lastname: Rodruigues
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Flora
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Patty
authors.initials: P
authors.lastname: Wai
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Vidya
authors.initials: V
authors.lastname: Pawar
authors.affiliation: Centre for Cancer Research and Cell Biology, Queen's University, Belfast, BT9 7BL, Northern Ireland, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: McDade
authors.affiliation: Nuclear Receptor Transcription Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, CB2 0RE, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Carroll
authors.affiliation: Institut Curie, INSERM U830, 75248 Paris, France.|Institut Curie, Department of Tumour Biology, 75248 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Stoppa-Lyonnet
authors.affiliation: Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham and Nottingham University Hospitals Trust, Nottingham, NG7 2UH, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: Department of Histopathology, School of Molecular Medical Sciences, University of Nottingham and Nottingham University Hospitals Trust, Nottingham, NG7 2UH, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, WC2A 3LY, UK.|UCL Cancer Institute, Huntley Street, London WC1E 6DD, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.affiliation: University Medical Centre Utrecht, 3584 CX Utrecht, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: van Diest
authors.affiliation: Institut Curie, INSERM U830, 75248 Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, QC, H2W 1S6, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.affiliation: Institut Curie, INSERM U830, 75248 Paris, France.|Institut Curie, Department of Tumour Biology, 75248 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: Institut Curie, INSERM U830, 75248 Paris, France.|Institut Curie, Department of Tumour Biology, 75248 Paris, France.
authors.forename: Marc Henri
authors.initials: MH
authors.lastname: Stern
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D049914:DNA Repair-Deficiency Disorders; D004273:DNA, Neoplasm / Q000032:analysis; D064550:Death-Associated Protein Kinases; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D023281:Genomics; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D011960:Receptors, Estrogen / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004273:DNA, Neoplasm; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D011960:Receptors, Estrogen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D033921:Vesicular Transport Proteins; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases