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The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

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Harvard

Wang, Y, Bernhardy, AJ, Cruz, C, Krais, JJ, Nacson, J, Nicolas, E, Peri, S, van der Gulden, H, van der Heijden, I, O'Brien, SW, Zhang, Y, Harrell, MI, Johnson, SF, Candido Dos Reis, FJ, Pharoah, PDP, Karlan, B, Gourley, C, Lambrechts, D, Chenevix-Trench, G, Olsson, H, Benitez, JJ, Greene, MH, Gore, M, Nussbaum, R, Sadetzki, S, Gayther, SA, Kjaer, SK, D'Andrea, AD, Shapiro, GI, Wiest, DL, Connolly, DC, Daly, MB, Swisher, EM, Bouwman, P, Jonkers, J, Balmaña, J, Serra, V, Johnson, N & kConFab Investigators 2016, 'The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin' Cancer Research, bind 76, nr. 9, s. 2778-90. https://doi.org/10.1158/0008-5472.CAN-16-0186

APA

CBE

Wang Y, Bernhardy AJ, Cruz C, Krais JJ, Nacson J, Nicolas E, Peri S, van der Gulden H, van der Heijden I, O'Brien SW, Zhang Y, Harrell MI, Johnson SF, Candido Dos Reis FJ, Pharoah PDP, Karlan B, Gourley C, Lambrechts D, Chenevix-Trench G, Olsson H, Benitez JJ, Greene MH, Gore M, Nussbaum R, Sadetzki S, Gayther SA, Kjaer SK, D'Andrea AD, Shapiro GI, Wiest DL, Connolly DC, Daly MB, Swisher EM, Bouwman P, Jonkers J, Balmaña J, Serra V, Johnson N, kConFab Investigators. 2016. The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Research. 76(9):2778-90. https://doi.org/10.1158/0008-5472.CAN-16-0186

MLA

Vancouver

Author

Wang, Yifan ; Bernhardy, Andrea J ; Cruz, Cristina ; Krais, John J ; Nacson, Joseph ; Nicolas, Emmanuelle ; Peri, Suraj ; van der Gulden, Hanneke ; van der Heijden, Ingrid ; O'Brien, Shane W ; Zhang, Yong ; Harrell, Maribel I ; Johnson, Shawn F ; Candido Dos Reis, Francisco J ; Pharoah, Paul D P ; Karlan, Beth ; Gourley, Charlie ; Lambrechts, Diether ; Chenevix-Trench, Georgia ; Olsson, Håkan ; Benitez, Javier J ; Greene, Mark H ; Gore, Martin ; Nussbaum, Robert ; Sadetzki, Siegal ; Gayther, Simon A ; Kjaer, Susanne K ; D'Andrea, Alan D ; Shapiro, Geoffrey I ; Wiest, David L ; Connolly, Denise C ; Daly, Mary B ; Swisher, Elizabeth M ; Bouwman, Peter ; Jonkers, Jos ; Balmaña, Judith ; Serra, Violeta ; Johnson, Neil ; kConFab Investigators. / The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. I: Cancer Research. 2016 ; Bind 76, Nr. 9. s. 2778-90.

Bibtex

@article{953f8ee6c32148b4a0b3cd78683a3dbe,
title = "The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin",
abstract = "Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. {\circledC}2016 AACR.",
keywords = "Journal Article",
author = "Yifan Wang and Bernhardy, {Andrea J} and Cristina Cruz and Krais, {John J} and Joseph Nacson and Emmanuelle Nicolas and Suraj Peri and {van der Gulden}, Hanneke and {van der Heijden}, Ingrid and O'Brien, {Shane W} and Yong Zhang and Harrell, {Maribel I} and Johnson, {Shawn F} and {Candido Dos Reis}, {Francisco J} and Pharoah, {Paul D P} and Beth Karlan and Charlie Gourley and Diether Lambrechts and Georgia Chenevix-Trench and H{\aa}kan Olsson and Benitez, {Javier J} and Greene, {Mark H} and Martin Gore and Robert Nussbaum and Siegal Sadetzki and Gayther, {Simon A} and Kjaer, {Susanne K} and D'Andrea, {Alan D} and Shapiro, {Geoffrey I} and Wiest, {David L} and Connolly, {Denise C} and Daly, {Mary B} and Swisher, {Elizabeth M} and Peter Bouwman and Jos Jonkers and Judith Balma{\~n}a and Violeta Serra and Neil Johnson and {kConFab Investigators}",
note = "{\circledC}2016 American Association for Cancer Research.",
year = "2016",
month = "5",
day = "1",
doi = "10.1158/0008-5472.CAN-16-0186",
language = "English",
volume = "76",
pages = "2778--90",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research (A A C R)",
number = "9",

}

RIS

TY - JOUR

T1 - The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin

AU - Wang, Yifan

AU - Bernhardy, Andrea J

AU - Cruz, Cristina

AU - Krais, John J

AU - Nacson, Joseph

AU - Nicolas, Emmanuelle

AU - Peri, Suraj

AU - van der Gulden, Hanneke

AU - van der Heijden, Ingrid

AU - O'Brien, Shane W

AU - Zhang, Yong

AU - Harrell, Maribel I

AU - Johnson, Shawn F

AU - Candido Dos Reis, Francisco J

AU - Pharoah, Paul D P

AU - Karlan, Beth

AU - Gourley, Charlie

AU - Lambrechts, Diether

AU - Chenevix-Trench, Georgia

AU - Olsson, Håkan

AU - Benitez, Javier J

AU - Greene, Mark H

AU - Gore, Martin

AU - Nussbaum, Robert

AU - Sadetzki, Siegal

AU - Gayther, Simon A

AU - Kjaer, Susanne K

AU - D'Andrea, Alan D

AU - Shapiro, Geoffrey I

AU - Wiest, David L

AU - Connolly, Denise C

AU - Daly, Mary B

AU - Swisher, Elizabeth M

AU - Bouwman, Peter

AU - Jonkers, Jos

AU - Balmaña, Judith

AU - Serra, Violeta

AU - Johnson, Neil

AU - kConFab Investigators

N1 - ©2016 American Association for Cancer Research.

PY - 2016/5/1

Y1 - 2016/5/1

N2 - Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.

AB - Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.

KW - Journal Article

U2 - 10.1158/0008-5472.CAN-16-0186

DO - 10.1158/0008-5472.CAN-16-0186

M3 - Journal article

VL - 76

SP - 2778

EP - 2790

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 9

ER -

ID: 49569260