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 Biswas; Barbara Godthelp; Josephine Dorsman; Peter E Clayton; Shyam K Sharan; Anthony D 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, 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

University of Manchester

Allbwn ymchwil: Cyfraniad at gyfnodolyn › Erthygl › adolygiad gan gymheiriaid

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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.

Iaith wreiddiol	Saesneg
Tudalennau (o-i)	e2875-e2875
Cyfnodolyn	Cell Death and Disease
Cyfrol	8
Rhif cyhoeddi	6
Dynodwyr Gwrthrych Digidol (DOIs)	https://doi.org/10.1038/cddis.2017.264
Statws	Cyhoeddwyd - 2017
Cyhoeddwyd yn allanol	Ie

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10.1038/cddis.2017.264Trwydded: CC BY

Dyfynnu hyn

Meyer, S., Stevens, A., Paredes, R., Schneider, M., Walker, M. J., Williamson, A. J. K., Gonzalez-Sanchez, M.-B., Smetsers, S., Dalal, V., Teng, H. Y., White, D. J., Taylor, S., Muter, J., Pierce, A., de Leonibus, C., Rockx, D. A. P., Rooimans, M. A., Spooncer, E., Stauffer, S., ... 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-e2875. https://doi.org/10.1038/cddis.2017.264

@article{058465ad99874d74855783d00b148e6e,

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 {\textquoteleft}BRCAness{\textquoteright} profile.",

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

year = "2017",

doi = "10.1038/cddis.2017.264",

language = "English",

volume = "8",

pages = "e2875--e2875",

journal = "Cell Death and Disease",

issn = "2041-4889",

publisher = "Springer Nature",

number = "6",

}

Meyer, S, Stevens, A, Paredes, R, Schneider, M, Walker, MJ, Williamson, AJK, Gonzalez-Sanchez, M-B, Smetsers, S, Dalal, V, Teng, HY, White, DJ, Taylor, S, Muter, J, Pierce, A, de Leonibus, C, Rockx, DAP, Rooimans, MA, Spooncer, E, Stauffer, S, Biswas, K, Godthelp, B, Dorsman, J, Clayton, PE, Sharan, SK & Whetton, AD 2017, 'Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption', Cell Death and Disease, cyfrol. 8, rhif 6, tt. e2875-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, Adam

AU - Paredes, Roberto

AU - Schneider, Marion

AU - Walker, Michael J

AU - Williamson, Andrew J K

AU - Gonzalez-Sanchez, Maria-Belen

AU - Smetsers, Stephanie

AU - Dalal, Vineet

AU - Teng, Hsiang Ying

AU - White, Daniel J

AU - Taylor, Sam

AU - Muter, Joanne

AU - Pierce, Andrew

AU - de Leonibus, Chiara

AU - Rockx, Davy A P

AU - Rooimans, Martin A

AU - Spooncer, Elaine

AU - Stauffer, Stacey

AU - Biswas, Kajal

AU - Godthelp, Barbara

AU - Dorsman, Josephine

AU - Clayton, Peter E

AU - Sharan, Shyam K

AU - Whetton, Anthony D

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

SP - e2875-e2875

JO - Cell Death and Disease

JF - Cell Death and Disease

IS - 6

ER -

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

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