Abstract 4022: BRCA1-like signature in triple negative breast cancers within the RATHER (Rational Therapy for Breast Cancer) Consortium.
Authors: Severson Tesa , Peeters Justine , Majewski Ian , Bosma Astrid , Chin Suet-Feung , Caldas Carlos , Simon Iris , Bernards Rene , Linn Sabine 
Published: August 2014

Background: More than 75% of BRCA1 mutated breast cancers are either triple negative (lacking estrogen, progesterone receptors and HER2 receptor overexpression), basal-like or both (1).

BRCA1 is required for proper function of the homologous recombination (HR)-mediated DNA repair pathway and deficiency results in genomic instability(2). BRCA1 mutated tumors have a specific pattern of alterations, which has been used to develop a BRCA1-like classifier to distinguish between BRCA1-like and breast cancers without BRCA1 deficiency (sporadic-like)(3). Previously it has been shown that over one third of tumors classified as BRCA1-like by comparative genomic hybridization (CGH) have no BRCA1 mutation or promoter methylation(4).

Methods: 135 triple negative breast cancer samples (fresh frozen) with long-term follow-up were collected from two institutes within the EU funded RATHER project. All samples were processed following one standard operating protocol to isolate RNA, DNA and protein of high quality. We collected BRCA1 mutation information by next generation sequencing, BRCA1-like classification by multiplex ligation-dependent probe amplification (MLPA) status which makes use of the most informative classifying regions from CGH and full genome expression data for all patients. We analyzed if tumors that classify as BRCA1-like with no mutation or methylation possess a mutation or dysregulation in another gene or genes involved in DNA repair, which is responsible for the BRCA1-like phenotype.

Results: In this patient cohort, 17 of the 135 TN patients had a BRCA1 mutation while 65 patients were classified as BRCA1-like. We have determined 15.4% of the BRCA1-like samples are BRCA1 mutated. Using whole genome expression analysis, we found a set of highly significant differentially expressed genes between the BRCA1-like and sporadic-like tumors. These genes are involved in virtually all biological processes including a selection of DNA repair genes. When performing supervised analysis on significantly differentially expressed DNA repair genes, we find two groups, one enriched for BRCA1-like status and one for sporadic-like status.

Conclusions: We have identified several genes not previously known to be involved in repair pathways which are significantly differentially expressed between the BRCA1-like and sporadic-like groups. Patients with tumors, which have DNA damage repair deficiencies, may be more susceptible to specific treatments such as PARP inhibitors.

Citation Format: Tesa Severson, Justine Peeters, Ian Majewski, Astrid Bosma, Suet-Feung Chin, Carlos Caldas, Iris Simon, Rene Bernards, Sabine Linn. BRCA1-like signature in triple negative breast cancers within the RATHER (Rational Therapy for Breast Cancer) Consortium. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4022. doi:10.1158/1538-7445.AM2013-4022