Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption

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.

Splicing factor proline- and glutamine-rich (SFPQ) protein regulates platinum response in ovarian cancer-modulating SRSF2 activity

“…Several reports suggest that alternative splicing of specific genes, such as BRCA1, BRCA2, BARD1, or ERCC1, can impact on the response of cancer cells to PT and some studies also suggest that this correlates with PT resistance in human cancer [23][24][25][26][27][28]. Accordingly, it has been proposed that evaluation of alternative splicing of selected genes could serve as prognostic marker in ovarian cancer [29].…”

Aberrant RNA Splicing in Cancer and Drug Resistance

“…Interestingly, PARPi resistance can be reversed with a small molecule inhibitor P1-B that suppresses the U2 snRNP spliceosome machinery, leading to a silencing of the splicing event responsible for generating BRCA1-∆11q and re-sensitization of cancer cells to PARPi treatment [ 125 ]. In addition, aberrant splicing of BRCA2 and chemoresistance has been reported in a recent study [ 143 ]. A novel splice variant BRCA2 ∆E5+7 , missing exons 5 and 7, encodes an in-frame protein isoform with an internal deletion of 55 amino acids compared to wild-type BCRA2.…”

“…A novel splice variant BRCA2 ∆E5+7 , missing exons 5 and 7, encodes an in-frame protein isoform with an internal deletion of 55 amino acids compared to wild-type BCRA2. Expression of this aberrant isoform has been associated with the acquisition of resistance to the DNA cross-linking drug mitomycin C [ 143 ].…”

Transcriptome-wide analysis and modelling of prognostic alternative splicing signatures in invasive breast cancer: a prospective clinical study

“…AS is also gaining much attention in therapy resistance. In chemotherapy, the BRCA2∆E5 + 7 and ∆40p53 isoforms perform acquisition of resistance to the DNA cross-linking drug mitomycin C 40 and cisplatin 41 , respectively. In other areas, the CD19-∆2 variant leads to loss of CAR recognition site to prevent CART-cell targeting/killing of B-ALL cells.…”