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

Stefan Meyer, Adam Stevens, Roberto Paredes, Marion Schneider, Michael J. Walker, Andrew J.K. Williamson, Maria Belen Gonzalez-Sanchez, Stephanie Smetsers, Vineet Dalal, Hsiang Ying Teng, Daniel J. White, Sam Taylor, Joanne Muter, Andrew Pierce, Chiara De Leonibus, Davy A.P. Rockx, Martin A. Rooimans, Elaine Spooncer, Stacey Stauffer, Kajal BiswasBarbara Godthelp, Josephine Dorsman, Peter E. Clayton, Shyam K. Sharan, Anthony D. Whetton

Research output: Contribution to journalArticleAcademicpeer-review

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 (BRCA2 δE5+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 â € BRCAness' profile.

Original languageEnglish
Article numbere2875
JournalCell Death and Disease
Volume8
Issue number6
DOIs
Publication statusPublished - 15 Jun 2017

Cite this

Meyer, S., Stevens, A., Paredes, R., Schneider, M., Walker, M. J., Williamson, A. J. K., ... Whetton, A. D. (2017). Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption. Cell Death and Disease, 8(6), [e2875]. https://doi.org/10.1038/cddis.2017.264