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 & 5 others Barbara 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
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. / Acquired cross-linker resistance associated with a novel spliced BRCA2 protein variant for molecular phenotyping of BRCA2 disruption. In: Cell Death and Disease. 2017 ; Vol. 8, No. 6.
@article{dd068f8dfdc34c4f84050af9969d69c4,
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 (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 {\^a} € BRCAness' profile.",
author = "Stefan Meyer and Adam Stevens and Roberto Paredes and Marion Schneider and Walker, {Michael J.} and Williamson, {Andrew J.K.} and Gonzalez-Sanchez, {Maria Belen} 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",
month = "6",
day = "15",
doi = "10.1038/cddis.2017.264",
language = "English",
volume = "8",
journal = "Cell death & disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "6",

}

Meyer, S, Stevens, A, Paredes, R, Schneider, M, Walker, MJ, Williamson, AJK, Gonzalez-Sanchez, MB, 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, vol. 8, no. 6, e2875. https://doi.org/10.1038/cddis.2017.264

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

In: Cell Death and Disease, Vol. 8, No. 6, e2875, 15.06.2017.

Research output: Contribution to journalArticleAcademicpeer-review

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 - 2017/6/15

Y1 - 2017/6/15

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 (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.

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 (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.

UR - http://www.scopus.com/inward/record.url?scp=85020861549&partnerID=8YFLogxK

U2 - 10.1038/cddis.2017.264

DO - 10.1038/cddis.2017.264

M3 - Article

VL - 8

JO - Cell death & disease

JF - Cell death & disease

SN - 2041-4889

IS - 6

M1 - e2875

ER -