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

Stefan Meyer; Frederick Stevens; Roberto Paredes; Marion Schneider; Michael Walker; Andrew Williamson; Maria Gonzalez-Sanchez; Stephanie Smetsers; Vineet Dalal; Hsiang-Ying Teng; Daniel White; Samuel Taylor; Joanne Muter; Andrew Pierce; Chiara De Leonibus; Davy AP Rockx; Martin Rooimans; Elaine Spooncer; Stacey Stauffer; Kajal Biswas; Barbara Godthelp; Josephine Dorsman; Peter Clayton; Shyam K. Sharan; Anthony Whetton

doi:10.1038/cddis.2017.264

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

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

Research output: Contribution to journal › Article › peer-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 (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.

Original language	English
Article number	e2875
Journal	CELL DEATH & DISEASE
Volume	8
Early online date	15 Jun 2017
DOIs	https://doi.org/10.1038/cddis.2017.264
Publication status	Published - 2017

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/cddis.2017.264Licence: CC BY

Manchester Molecular Pathology Innovation Centre (MMPathIC): Bridging the Gap Between Biomarker Discovery and Health and Wealth.
Freemont, A. (PI), Ananiadou, S. (CoI), Barton, A. (CoI), Black, G. (CoI), Bruce, I. (CoI), Buchan, I. (CoI), Byers, R. (CoI), Dive, C. (CoI), Goodacre, R. (CoI), Griffiths, C. (CoI), Hoyland, J. (CoI), Payne, K. (CoI), Radford, J. (CoI) & Whetton, A. (CoI)
1/10/15 → 31/03/21
Project: Research

Cite this

Meyer, S., Stevens, F., Paredes, R., Schneider, M., Walker, M., Williamson, A., Gonzalez-Sanchez, M., Smetsers, S., Dalal, V., Teng, H.-Y., White, D., Taylor, S., Muter, J., Pierce, A., De Leonibus, C., Rockx, D. AP., Rooimans, M., Spooncer, E., Stauffer, S., ... Whetton, A. (2017). Acquired cross linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption. CELL DEATH & DISEASE, 8, Article e2875. https://doi.org/10.1038/cddis.2017.264

@article{a0f4e8784723454391a40a053e8d8e35,

title = "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.",

author = "Stefan Meyer and Frederick Stevens and Roberto Paredes and Marion Schneider and Michael Walker and Andrew Williamson and Maria Gonzalez-Sanchez and Stephanie Smetsers and Vineet Dalal and Hsiang-Ying Teng and Daniel White and Samuel Taylor and Joanne Muter and Andrew Pierce and {De Leonibus}, Chiara and Rockx, {Davy AP} and Martin Rooimans and Elaine Spooncer and Stacey Stauffer and Kajal Biswas and Barbara Godthelp and Josephine Dorsman and Peter Clayton and Sharan, {Shyam K.} and Anthony Whetton",

year = "2017",

doi = "10.1038/cddis.2017.264",

language = "English",

volume = "8",

journal = "CELL DEATH & DISEASE",

issn = "2041-4889",

publisher = "Springer Nature",

}

Meyer, S , Stevens, F, Paredes, R, Schneider, M, Walker, M, Williamson, A, Gonzalez-Sanchez, M, Smetsers, S, Dalal, V, Teng, H-Y, White, D, Taylor, S, Muter, J, Pierce, A, De Leonibus, C, Rockx, DAP, Rooimans, M, Spooncer, E, Stauffer, S, Biswas, K, Godthelp, B, Dorsman, J, Clayton, P, Sharan, SK & Whetton, A 2017, 'Acquired cross linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption', CELL DEATH & DISEASE, vol. 8, e2875. https://doi.org/10.1038/cddis.2017.264

TY - JOUR

T1 - Acquired cross linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption

AU - Meyer, Stefan

AU - Stevens, Frederick

AU - Paredes, Roberto

AU - Schneider, Marion

AU - Walker, Michael

AU - Williamson, Andrew

AU - Gonzalez-Sanchez, Maria

AU - Smetsers, Stephanie

AU - Dalal, Vineet

AU - Teng, Hsiang-Ying

AU - White, Daniel

AU - Taylor, Samuel

AU - Muter, Joanne

AU - Pierce, Andrew

AU - De Leonibus, Chiara

AU - Rockx, Davy AP

AU - Rooimans, Martin

AU - Spooncer, Elaine

AU - Stauffer, Stacey

AU - Biswas, Kajal

AU - Godthelp, Barbara

AU - Dorsman, Josephine

AU - Clayton, Peter

AU - Sharan, Shyam K.

AU - Whetton, Anthony

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1038/cddis.2017.264

DO - 10.1038/cddis.2017.264

M3 - Article

SN - 2041-4889

VL - 8

JO - CELL DEATH & DISEASE

JF - CELL DEATH & DISEASE

M1 - e2875

ER -

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

Abstract

Research Beacons, Institutes and Platforms

UN SDGs

Access to Document

Fingerprint

Projects

Manchester Molecular Pathology Innovation Centre (MMPathIC): Bridging the Gap Between Biomarker Discovery and Health and Wealth.

Cite this