Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors.
David A. Quigley,Joshi J. Alumkal,Alexander W. Wyatt,Vishal Kothari,Adam Foye,Paul Lloyd,Rahul Aggarwal,Won Kim,Eric Lu,Jacob Schwartzman,Kevin Beja,Matti Annala,Rajdeep Das,Morgan E. Diolaiti,Colin C. Pritchard,George Thomas,Scott A. Tomlins,Karen E. Knudsen,Christopher J. Lord,Charles J. Ryan,Jack F. Youngren,Tomasz M. Beer,Alan Ashworth,Eric J. Small,Felix Y. Feng +24 more
TLDR
BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib are identified and it is shown that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PAR Pi resistance.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.read more
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Prostate cancer in the era of “Omic” medicine: recognizing the importance of DNA damage repair pathways
TL;DR: The role of DDR mutations in prostate cancer, including deficiencies in homologous repair and mismatch repair (MMR), and how this information is revolutionizing the treatment landscape are discussed are discussed.
Journal ArticleDOI
Comprehensive Analysis of Somatic Reversion Mutations in Homologous Recombination Repair (HRR) Genes in A Large Cohort of Chinese Pan-cancer Patients
Hong Zong,Jian Zhang,Zhengyang Xu,Jia-zhen Pan,Rong Wang,Jinming Han,Miao Jiang,Ruiping Ren,L. Zang,Haitao Wang,Wen-Ming Cao +10 more
TL;DR: This study comprehensively depicts the prevalence and characteristics of HRR reversion mutation of germline mutations in an unselected Chinese pan-cancer cohort and suggests that monitoring HRR mutation status along the disease course could be beneficial especially for informing resistance mechanisms and guiding subsequent therapies.
Journal ArticleDOI
The role of liquid biopsies in prostate cancer management
Chi-Ju Kim,Chi-Ju Kim,Liang Dong,Liang Dong,Sarah R. Amend,Yoon-Kyoung Cho,Kenneth J. Pienta +6 more
TL;DR: In this article, a review describes recent advancements in isolation and detection technology and the strength and weaknesses of the three circulating biomarkers (CTC, extracellular vesicles (EVs), and circulating tumor DNA (ctDNA).
Journal ArticleDOI
Opportunities and Challenges in Genomic Sequencing for Precision Cancer Care
Michael L. Cheng,David B. Solit +1 more
TL;DR: Next-generation sequencing can robustly define MSI-H or dMMR status through mutational signature analysis and simultaneously identify individual genetic variants that are predictive biomarkers of drug sensitivity, thus reducing the quantity of tissue needed for comprehensive molecular characterization.
Journal ArticleDOI
PARP inhibitors and breast cancer: highlights and hang-ups
TL;DR: The task ahead is now to optimise PARPi therapy, identifying the ideal drug combinations to use with these agents as well as establishing the optimal stage and scheduling that should be used to achieve maximum benefit and manage the emergence of resistance.
References
More filters
Journal Article
R: A language and environment for statistical computing.
TL;DR: Copyright (©) 1999–2012 R Foundation for Statistical Computing; permission is granted to make and distribute verbatim copies of this manual provided the copyright notice and permission notice are preserved on all copies.
Journal ArticleDOI
The Sequence Alignment/Map format and SAMtools
Heng Li,Bob Handsaker,Alec Wysoker,T. J. Fennell,Jue Ruan,Nils Homer,Gabor T. Marth,Gonçalo R. Abecasis,Richard Durbin +8 more
TL;DR: SAMtools as discussed by the authors implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments.
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
BEDTools: a flexible suite of utilities for comparing genomic features
Aaron R. Quinlan,Ira M. Hall +1 more
TL;DR: A new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format, which allows the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks.
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