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

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 McDadeJason 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

Research output: Contribution to journalArticle

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).

Original languageEnglish (US)
Pages (from-to)29-41
Number of pages13
JournalJournal of Pathology
Volume227
Issue number1
DOIs
StatePublished - May 2012
Externally publishedYes

Fingerprint

High-Throughput Nucleotide Sequencing
Estrogen Receptors
Germ-Line Mutation
Genome
Breast Neoplasms
Recombinational DNA Repair
Alleles
Tumor Suppressor Proteins
Neoplasms
Mutation
Neoplasm Genes
Cell Cycle Checkpoints
Base Pairing
Ovarian Neoplasms
Cohort Studies
Phenotype
DNA

Keywords

  • BRCA1
  • Breast cancer
  • Mutation
  • Next generation sequencing
  • Tumour suppressor genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Natrajan, R., Mackay, A., Lambros, M. B., Weigelt, B., Wilkerson, P. M., Manie, E., ... Reis-Filho, J. S. (2012). A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. Journal of Pathology, 227(1), 29-41. https://doi.org/10.1002/path.4003

A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. / Natrajan, Rachael; Mackay, Alan; Lambros, Maryou B.; Weigelt, Britta; Wilkerson, Paul M.; Manie, Elodie; Grigoriadis, Anita; A'Hern, Roger; Van Der Groep, Petra; Kozarewa, Iwanka; Popova, Tatiana; Mariani, Odette; Turajlic, Samra; Furney, Simon J.; Marais, Richard; Rodruigues, Daniel Nava; Flora, Adriana C.; Wai, Patty; Pawar, Vidya; McDade, Simon; Carroll, Jason; Stoppa-Lyonnet, Dominique; Green, Andrew R.; Ellis, Ian O.; Swanton, Charles; Van Diest, Paul; Delattre, Olivier; Lord, Christopher J.; Foulkes, William D.; Vincent-Salomon, Anne; Ashworth, Alan; Stern, Marc Henri; Reis-Filho, Jorge S.

In: Journal of Pathology, Vol. 227, No. 1, 05.2012, p. 29-41.

Research output: Contribution to journalArticle

Natrajan, R, Mackay, A, Lambros, MB, Weigelt, B, Wilkerson, PM, Manie, E, Grigoriadis, A, A'Hern, R, Van Der Groep, P, Kozarewa, I, Popova, T, Mariani, O, Turajlic, S, Furney, SJ, Marais, R, Rodruigues, DN, Flora, AC, Wai, P, Pawar, V, McDade, S, Carroll, J, Stoppa-Lyonnet, D, Green, AR, Ellis, IO, Swanton, C, Van Diest, P, Delattre, O, Lord, CJ, Foulkes, WD, Vincent-Salomon, A, Ashworth, A, Stern, MH & Reis-Filho, JS 2012, 'A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers', Journal of Pathology, vol. 227, no. 1, pp. 29-41. https://doi.org/10.1002/path.4003
Natrajan, Rachael ; Mackay, Alan ; Lambros, Maryou B. ; Weigelt, Britta ; Wilkerson, Paul M. ; Manie, Elodie ; Grigoriadis, Anita ; A'Hern, Roger ; Van Der Groep, Petra ; Kozarewa, Iwanka ; Popova, Tatiana ; Mariani, Odette ; Turajlic, Samra ; Furney, Simon J. ; Marais, Richard ; Rodruigues, Daniel Nava ; Flora, Adriana C. ; Wai, Patty ; Pawar, Vidya ; McDade, Simon ; Carroll, Jason ; Stoppa-Lyonnet, Dominique ; Green, Andrew R. ; Ellis, Ian O. ; Swanton, Charles ; Van Diest, Paul ; Delattre, Olivier ; Lord, Christopher J. ; Foulkes, William D. ; Vincent-Salomon, Anne ; Ashworth, Alan ; Stern, Marc Henri ; Reis-Filho, Jorge S. / A whole-genome massively parallel sequencing analysis of BRCA1 mutant oestrogen receptor-negative and -positive breast cancers. In: Journal of Pathology. 2012 ; Vol. 227, No. 1. pp. 29-41.
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