Document Detail

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers.
MedLine Citation:
PMID:  22362584     Owner:  NLM     Status:  MEDLINE    
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).
Rachael Natrajan; Alan Mackay; Maryou B Lambros; Britta Weigelt; Paul M Wilkerson; Elodie Manie; Anita Grigoriadis; Roger A'hern; Petra van der Groep; Iwanka Kozarewa; Tatiana Popova; Odette Mariani; Samra Turajlic; Simon J Furney; Richard Marais; Daniel-Nava Rodruigues; Adriana C Flora; Patty Wai; Vidya Pawar; Simon McDade; Jason Carroll; Dominique Stoppa-Lyonnet; Andrew R Green; Ian O Ellis; Charles Swanton; Paul van Diest; Olivier Delattre; Christopher J Lord; William D Foulkes; Anne Vincent-Salomon; Alan Ashworth; Marc Henri Stern; Jorge S Reis-Filho
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Publication Detail:
Type:  Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't     Date:  2012-02-23
Journal Detail:
Title:  The Journal of pathology     Volume:  227     ISSN:  1096-9896     ISO Abbreviation:  J. Pathol.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-04     Completed Date:  2012-05-22     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  29-41     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MeSH Terms
Apoptosis Regulatory Proteins / genetics
BRCA1 Protein / genetics*,  metabolism
Breast Neoplasms / diagnosis,  genetics*,  metabolism
Calcium-Calmodulin-Dependent Protein Kinases / genetics
Carcinoma, Ductal, Breast / diagnosis,  genetics*,  metabolism
DNA Mutational Analysis
DNA Repair-Deficiency Disorders
DNA, Neoplasm / analysis
Death-Associated Protein Kinases
GATA4 Transcription Factor / genetics
Germ-Line Mutation*
Loss of Heterozygosity
Middle Aged
Receptors, Estrogen / metabolism*
Tumor Suppressor Protein p53 / genetics,  metabolism
Vesicular Transport Proteins / genetics
Grant Support
G0701935//Medical Research Council; //Wellcome Trust
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BRCA1 Protein; 0/BRCA1 protein, human; 0/DNA, Neoplasm; 0/GATA4 Transcription Factor; 0/GATA4 protein, human; 0/Receptors, Estrogen; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/Vesicular Transport Proteins; EC protein, human; EC Protein Kinases; EC Protein Kinases
Comment In:
J Pathol. 2012 Jul;227(3):267-9   [PMID:  22431191 ]

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