Methylation of All BRCA1 Copies Predicts Response to the PARP Inhibitor Rucaparib in Ovarian Carcinoma

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Sep 30

PMID 30266954

Citations 143

Authors

Olga Kondrashova

Monique Topp

Ksenija Nesic

Elizabeth Lieschke

Gwo-Yaw Ho

Maria I Harrell

Giada V Zapparoli

Alison Hadley

Robert Holian

Emma Boehm

Valerie Heong

Elaine Sanij

Richard B Pearson

John J Krais

Neil Johnson

Orla McNally

Sumitra Ananda

Kathryn Alsop

Karla J Hutt

Scott H Kaufmann

Kevin K Lin

Thomas C Harding

Nadia Traficante

Anna DeFazio

Iain A McNeish

David D Bowtell

Elizabeth M Swisher

Alexander Dobrovic

Matthew J Wakefield

Clare L Scott

Affiliations

Soon will be listed here.

Abstract

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-naive 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 BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.

Citing Articles

Combination therapy with Chicoric acid and PD-1/PD-L1 blockade improves the immunotherapy response in patient-derived ovarian cancer xenograft model.

Lan H, Zhu J, Hou H, Zhang C, Huo X, Zhang Y Cell Commun Signal. 2025; 23(1):137.

PMID: 40087780 DOI: 10.1186/s12964-025-02146-7.

A Rapid and Reliable Test for Promoter Hypermethylation in Paraffin Tissue Using Pyrosequencing.

Bacares R, Soslow R, Olvera N, Levine D, Zhang L Diagnostics (Basel). 2025; 15(5).

PMID: 40075848 PMC: 11898801. DOI: 10.3390/diagnostics15050601.

Predictive biomarkers for the efficacy of PARP inhibitors in ovarian cancer: an updated systematic review.

Wang Y, Allen I, Funingana G, Tischkowitz M, Joko-Fru Y BJC Rep. 2025; 3(1):14.

PMID: 40069561 PMC: 11897386. DOI: 10.1038/s44276-025-00122-9.

The Landscape of PARP Inhibitors in Solid Cancers.

Muzzana M, Broggini M, Damia G Onco Targets Ther. 2025; 18:297-317.

PMID: 40051775 PMC: 11884256. DOI: 10.2147/OTT.S499226.

Targeting the 8-oxodG Base Excision Repair Pathway for Cancer Therapy.

Piscone A, Gorini F, Ambrosio S, Noviello A, Scala G, Majello B Cells. 2025; 14(2).

PMID: 39851540 PMC: 11764161. DOI: 10.3390/cells14020112.

References

Alsop K, Fereday S, Meldrum C, DeFazio A, Emmanuel C, George J . BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol. 2012; 30(21):2654-63. PMC: 3413277. DOI: 10.1200/JCO.2011.39.8545. View

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

George J, Alsop K, Etemadmoghadam D, Hondow H, Mikeska T, Dobrovic A . Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013; 19(13):3474-84. DOI: 10.1158/1078-0432.CCR-13-0066. View

Lheureux S, Lai Z, Dougherty B, Runswick S, Hodgson D, Timms K . Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization. Clin Cancer Res. 2017; 23(15):4086-4094. DOI: 10.1158/1078-0432.CCR-16-2615. View

Wong E, Southey M, Fox S, Brown M, Dowty J, Jenkins M . Constitutional methylation of the BRCA1 promoter is specifically associated with BRCA1 mutation-associated pathology in early-onset breast cancer. Cancer Prev Res (Phila). 2010; 4(1):23-33. PMC: 4030007. DOI: 10.1158/1940-6207.CAPR-10-0212. View

Schilder R, Hall L, Monks A, Handel L, Fornace Jr A, Ozols R . Metallothionein gene expression and resistance to cisplatin in human ovarian cancer. Int J Cancer. 1990; 45(3):416-22. DOI: 10.1002/ijc.2910450306. View

Abkevich V, Timms K, Hennessy B, Potter J, Carey M, Meyer L . Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012; 107(10):1776-82. PMC: 3493866. DOI: 10.1038/bjc.2012.451. View

Norquist B, Harrell M, Brady M, Walsh T, Lee M, Gulsuner S . Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016; 2(4):482-90. PMC: 4845939. DOI: 10.1001/jamaoncol.2015.5495. View

Bianco T, Chenevix-Trench G, Walsh D, Cooper J, Dobrovic A . Tumour-specific distribution of BRCA1 promoter region methylation supports a pathogenetic role in breast and ovarian cancer. Carcinogenesis. 2000; 21(2):147-51. DOI: 10.1093/carcin/21.2.147. View

10.

Coleman R, Oza A, Lorusso D, Aghajanian C, Oaknin A, Dean A . Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 390(10106):1949-1961. PMC: 5901715. DOI: 10.1016/S0140-6736(17)32440-6. View

11.

Esteller M, Silva J, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E . Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst. 2000; 92(7):564-9. DOI: 10.1093/jnci/92.7.564. View

12.

Matulonis U, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G . Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy. Cancer. 2016; 122(12):1844-52. DOI: 10.1002/cncr.29995. View

13.

Swisher E, Gonzalez R, Taniguchi T, Garcia R, Walsh T, Goff B . Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas. Mol Cancer. 2009; 8:48. PMC: 2719582. DOI: 10.1186/1476-4598-8-48. View

14.

Dobrovic A, Simpfendorfer D . Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res. 1997; 57(16):3347-50. View

15.

Topp M, Hartley L, Cook M, Heong V, Boehm E, McShane L . Molecular correlates of platinum response in human high-grade serous ovarian cancer patient-derived xenografts. Mol Oncol. 2014; 8(3):656-68. PMC: 4400120. DOI: 10.1016/j.molonc.2014.01.008. View

16.

Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G . Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014; 15(8):852-61. DOI: 10.1016/S1470-2045(14)70228-1. View

17.

Fong P, Boss D, Yap T, Tutt A, Wu P, Mergui-Roelvink M . Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009; 361(2):123-34. DOI: 10.1056/NEJMoa0900212. View

18.

Mirza M, Monk B, Herrstedt J, Oza A, Mahner S, Redondo A . Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016; 375(22):2154-2164. DOI: 10.1056/NEJMoa1611310. View

19.

Kondrashova O, Nguyen M, Shield-Artin K, Tinker A, Teng N, Harrell M . Secondary Somatic Mutations Restoring and Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov. 2017; 7(9):984-998. PMC: 5612362. DOI: 10.1158/2159-8290.CD-17-0419. View

20.

Swisher E, Lin K, Oza A, Scott C, Giordano H, Sun J . Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016; 18(1):75-87. DOI: 10.1016/S1470-2045(16)30559-9. View