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

• Published in: Cell death & disease 2017-06, Vol.8 (6), p.e2875-e2875
• Main Authors: Meyer, Stefan, Stevens, Adam, Paredes, Roberto, Schneider, Marion, Walker, Michael J, Williamson, Andrew J K, Gonzalez-Sanchez, Maria-Belen, Smetsers, Stephanie, Dalal, Vineet, Teng, Hsiang Ying, White, Daniel J, Taylor, Sam, Muter, Joanne, Pierce, Andrew, de Leonibus, Chiara, Rockx, Davy A P, Rooimans, Martin A, Spooncer, Elaine, Stauffer, Stacey, Biswas, Kajal, Godthelp, Barbara, Dorsman, Josephine, Clayton, Peter E, Sharan, Shyam K, Whetton, Anthony D
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 14; 14/1; 38; 38/1; 38/61; 38/90; 45; 45/29; 631/67/1059/2326; 631/67/1059/99; 631/67/1517/1709; 692/699/1541/13; 82; 82/58; 82/83; Acute myeloid leukemia; Alternative Splicing; Anemia; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; BRCA2 protein; BRCA2 Protein - genetics; BRCA2 Protein - metabolism; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Biology; Cell Culture; Cell Line, Tumor; Chromatin remodeling; DNA Damage; Drug Resistance, Neoplasm; Exons; Fanconi Anemia - drug therapy; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi syndrome; Female; Genes, BRCA2; Genetic Predisposition to Disease; Genotype & phenotype; Homologous recombination; Humans; Hypersensitivity; Immunology; Introns; K562 Cells; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Life Sciences; Mice; Mutation; Myeloid leukemia; Neoplasm Recurrence, Local; Original; original-article; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Phenotype; Phenotyping; Proteins; Proteomics; RNA Splicing; Splicing; Transcription; Transcription, Genetic
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.264

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 ‘ BRCAness’ profile.