dc.contributor.author | Quigley, D | |
dc.contributor.author | Alumkal, JJ | |
dc.contributor.author | Wyatt, AW | |
dc.contributor.author | Kothari, V | |
dc.contributor.author | Foye, A | |
dc.contributor.author | Lloyd, P | |
dc.contributor.author | Aggarwal, R | |
dc.contributor.author | Kim, W | |
dc.contributor.author | Lu, E | |
dc.contributor.author | Schwartzman, J | |
dc.contributor.author | Beja, K | |
dc.contributor.author | Annala, M | |
dc.contributor.author | Das, R | |
dc.contributor.author | Diolaiti, M | |
dc.contributor.author | Pritchard, C | |
dc.contributor.author | Thomas, G | |
dc.contributor.author | Tomlins, S | |
dc.contributor.author | Knudsen, K | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Ryan, C | |
dc.contributor.author | Youngren, J | |
dc.contributor.author | Beer, TM | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Small, EJ | |
dc.contributor.author | Feng, FY | |
dc.date.accessioned | 2020-09-21T15:48:55Z | |
dc.date.issued | 2017-09-01 | |
dc.identifier.citation | Cancer discovery, 2017, 7 (9), pp. 999 - 1005 | |
dc.identifier.issn | 2159-8274 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4076 | |
dc.identifier.eissn | 2159-8290 | |
dc.identifier.doi | 10.1158/2159-8290.cd-17-0146 | |
dc.description.abstract | Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2 HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.Significance: The mechanisms of clinical resistance to PARPi in DNA repair-deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999-1005. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Goodall et al., p. 1006This article is highlighted in the In This Issue feature, p. 920. | |
dc.format | Print-Electronic | |
dc.format.extent | 999 - 1005 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Prostatic Neoplasms | |
dc.subject | Piperazines | |
dc.subject | Phthalazines | |
dc.subject | BRCA2 Protein | |
dc.subject | Antineoplastic Agents | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Germ-Line Mutation | |
dc.subject | Male | |
dc.subject | DNA Copy Number Variations | |
dc.subject | Poly(ADP-ribose) Polymerase Inhibitors | |
dc.subject | Whole Exome Sequencing | |
dc.subject | Cell-Free Nucleic Acids | |
dc.title | Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-04-26 | |
rioxxterms.versionofrecord | 10.1158/2159-8290.cd-17-0146 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-09 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer discovery | |
pubs.issue | 9 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.publication-status | Published | |
pubs.volume | 7 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Lord, Christopher | |