Abstract
BRCA2 encodes a protein with a fundamental role in homologous recombination that is essential for normal development. Carrier status of mutations in BRCA2 is associated with familial breast and ovarian cancer, while bi-allelic BRCA2 mutations can cause Fanconi anemia (FA), a cancer predisposition syndrome with cellular cross-linker hypersensitivity. Cancers associated with BRCA2 mutations can acquire chemo-resistance on relapse. We modeled acquired cross-linker resistance with an FA-derived BRCA2-mutated acute myeloid leukemia (AML) platform. Associated with acquired cross-linker resistance was the expression of a functional BRCA2 protein variant lacking exon 5 and exon 7 (BRCA2ΔE5+7), implying a role for BRCA2 splicing for acquired chemo-resistance. Integrated network analysis of transcriptomic and proteomic differences for phenotyping of BRCA2 disruption infers impact on transcription and chromatin remodeling in addition to the DNA damage response. The striking overlap with transcriptional profiles of FA patient hematopoiesis and BRCA mutation associated ovarian cancer helps define and explicate the ‘BRCAness’ profile.
Highlights
BRCA2 mutation carrier status is linked to familial breast and ovarian cancer (HBOC).[1]
The cellular phenotype associated with BRCA2 disruption includes the FAcharacteristic cross-linker sensitivity, the basis for targeted therapeutic approaches applying the concept of synthetic lethality.[8]
Having identified a novel BRCA2 splice isoform associated with phenotypic reversion, we confirmed previously reported data with respect to single observations in BRCA2 mutation associated tumors, such as dependence of BRCA2 function for nuclear accumulation of RAD51,34,35 or impaired phosphorylation of Nibrin, which has been previously observed associated with defects in the Fanconi anemia (FA)/BRCA pathway,[36] by mass spectrometry and western blot analysis
Summary
BRCA2 mutation carrier status is linked to familial breast and ovarian cancer (HBOC).[1]. Phenotypic reversion and acquired MMC resistance in these cells is associated with a novel spliced BRCA2 transcript in the MMC-resistant derivate clone, which generates a novel and functional BRCA2 protein variant. This platform is used for further delineation of the ‘BRCAness’ phenotype using transcriptomic, proteomic and phosphoproteomic differences in comparison to acquired cross-linker resistance. Tel: +44 161 446 3094; Fax: +44 161 446 3090; Received 01.12.16; revised 29.3.17; accepted 05.5.17; Edited by R Aqeilan clinical samples, using expression profiles of bone marrow from FA patients and the ‘BRCAness’ signature of ovarian cancer, carries important clinical and biological implications
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