Imperial College London
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ProfessorIainMcNeish

Faculty of Medicine, Department of Surgery & Cancer

Chair in Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2185i.mcneish Website

 
 
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Assistant

 

Ms Sophie Lions +44 (0)20 7594 2792

 
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Location

 

G036Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{McNeish:2018:10.1038/s41467-018-05564-z,
author = {McNeish, IA and Kondrashova, O and Topp, M and Nesic, K and Lieschke, E and Ho, G-Y and Harrell, MI and Zapparoli, GV and Hadley, A and Holian, R and Boehm, E and Heong, V and Sanij, E and Pearson, RB and Krais, JJ and Johnson, N and McNally, O and Ananda, S and Alsop, K and Hutt, KJ and Kaufmann, SH and Lin, KK and Harding, TC and Traficante, N and DeFazio, A and Bowtell, DD and Swisher, EM and Dobrovic, A and Wakefield, MJ and Scott, CL},
doi = {10.1038/s41467-018-05564-z},
journal = {Nature Communications},
title = {Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma},
url = {http://dx.doi.org/10.1038/s41467-018-05564-z},
volume = {9},
year = {2018}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Accurately  identifying  patients  with  high-grade serous  ovarian  carcinoma  (HGSOC)  who  respond  to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show  that  quantitative BRCA1  methylation  analysis  provides  new  insight  into  PARPi  response  in preclinical  models  and  ovarian  cancer  patients.  The  response  of  12  HGSOC  patient-derived  xenografts  (PDX)  to  the  PARPi  rucaparib  was  assessed,  with  variable  dose-dependent  responses  observed  in  chemo-naïve BRCA1/2-mutated  PDX,  and  no  responses  in  PDX  lacking  DNA  repair  pathway   defects.   Among  BRCA1-methylated   PDX,   silencing   of   all  BRCA1  copies   predicts   rucaparib  response,  whilst  heterozygous  methylation  is  associated  with  resistance.  Analysis  of  21  BRCA1-methylated  platinum-sensitive  recurrent  HGSOC  (ARIEL2  Part  1  trial)  confirmed  that  homozygous  or  hemizygous  BRCA1  methylation  predicts  rucaparib  clinical  response,  and  that  methylation  loss  can  occur  after  exposure  to  chemotherapy.  Accordingly,  quantitative  BRCA1methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit and facilitate tailoring of PARPi therapy.
AU  - McNeish,IA
AU  - Kondrashova,O
AU  - Topp,M
AU  - Nesic,K
AU  - Lieschke,E
AU  - Ho,G-Y
AU  - Harrell,MI
AU  - Zapparoli,GV
AU  - Hadley,A
AU  - Holian,R
AU  - Boehm,E
AU  - Heong,V
AU  - Sanij,E
AU  - Pearson,RB
AU  - Krais,JJ
AU  - Johnson,N
AU  - McNally,O
AU  - Ananda,S
AU  - Alsop,K
AU  - Hutt,KJ
AU  - Kaufmann,SH
AU  - Lin,KK
AU  - Harding,TC
AU  - Traficante,N
AU  - DeFazio,A
AU  - Bowtell,DD
AU  - Swisher,EM
AU  - Dobrovic,A
AU  - Wakefield,MJ
AU  - Scott,CL
DO  - 10.1038/s41467-018-05564-z
PY  - 2018///
SN  - 2041-1723
TI  - Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/s41467-018-05564-z
UR  - http://hdl.handle.net/10044/1/61797
VL  - 9
ER  -
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