Analysis of Circulating Cell-Free DnA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors

被引：230

作者：

Quigley, David ^{[1
,2
]}

Alumkal, Joshi J. ^{[3
,4
]}

Wyatt, Alexander W. ^{[5
]}

Kothari, Vishal ^{[1
,6
]}

Foye, Adam ^{[1
,7
]}

Lloyd, Paul ^{[1
,7
]}

Aggarwal, Rahul ^{[1
,7
]}

Kim, Won ^{[1
,7
]}

Lu, Eric ^{[3
]}

Schwartzman, Jacob ^{[3
]}

Beja, Kevin ^{[5
]}

Annala, Matti ^{[5
,8
]}

Das, Rajdeep ^{[1
,6
]}

Diolaiti, Morgan ^{[1
]}

Pritchard, Colin ^{[9
]}

Thomas, George ^{[3
,10
]}

Tomlins, Scott ^{[11
]}

Knudsen, Karen ^{[12
]}

Lord, Christopher J. ^{[13
,14
]}

Ryan, Charles ^{[1
,7
]}

Youngren, Jack ^{[1
,7
]}

Beer, Tomasz M. ^{[3
]}

Ashworth, Alan ^{[1
,15
]}

Small, Eric J. ^{[1
,7
]}

Feng, Felix Y. ^{[1
,6
]}

机构：

[1] UCSF, Helen Diller Family Comprehens Canc Ctr, Box 0128, San Francisco, CA 94158 USA

[2] UCSF, Dept Epidemiol & Biostat, San Francisco, CA USA

[3] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[4] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[5] Univ British Columbia, Dept Urol Sci, Vancouver Prostate Ctr, Vancouver, BC, Canada

[6] UCSF, Dept Radiat Oncol, San Francisco, CA USA

[7] UCSF, Div Hematol & Oncol, San Francisco, CA USA

[8] Univ Tampere, Inst Biosci & Med Technol, Tampere, Finland

[9] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA

[10] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[11] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA

[12] Thomas Jefferson Univ, Sidney Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA

[13] Inst Canc Res, CRUK Gene Funct Lab, London, England

[14] Inst Canc Res, Breast Canc Now Res Ctr, London, England

[15] UCSF, Dept Med, San Francisco, CA USA

来源：

CANCER DISCOVERY | 2017年 / 7卷 / 09期

关键词：

TUMORS;

D O I：

10.1158/2159-8290.CD-17-0146

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2017 AACR.

引用

页码：999 / 1005

页数：7

共 23 条

[1] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[2]

[Anonymous], 2012, R LANG ENV STAT COMP

[3]

Breast Canc Linkage Consortium, 1999, JNCI-J NATL CANCER I, V91, P1310

[4] Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase [J].

Bryant, HE ;

Schultz, N ;

Thomas, HD ;

Parker, KM ;

Flower, D ;

Lopez, E ;

Kyle, S ;

Meuth, M ;

Curtin, NJ ;

Helleday, T .

NATURE, 2005, 434 (7035) :913-917

[5] Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer [J].

Castro, Elena ;

Goh, Chee ;

Olmos, David ;

Saunders, Ed ;

Leongamornlert, Daniel ;

Tymrakiewicz, Malgorzata ;

Mahmud, Nadiya ;

Dadaev, Tokhir ;

Govindasami, Koveela ;

Guy, Michelle ;

Sawyer, Emma ;

Wilkinson, Rosemary ;

Ardern-Jones, Audrey ;

Ellis, Steve ;

Frost, Debra ;

Peock, Susan ;

Evans, D. Gareth ;

Tischkowitz, Marc ;

Cole, Trevor ;

Davidson, Rosemarie ;

Eccles, Diana ;

Brewer, Carole ;

Douglas, Fiona ;

Porteous, Mary E. ;

Donaldson, Alan ;

Dorkins, Huw ;

Izatt, Louise ;

Cook, Jackie ;

Hodgson, Shirley ;

Kennedy, M. John ;

Side, Lucy E. ;

Eason, Jacqueline ;

Murray, Alex ;

Antoniou, Antonis C. ;

Easton, Douglas F. ;

Kote-Jarai, Zsofia ;

Eeles, Rosalind .

JOURNAL OF CLINICAL ONCOLOGY, 2013, 31 (14) :1748-+

[6] Reversion of BRCA1/2 Germline Mutations Detected in Circulating Tumor DNA From Patients With High-Grade Serous Ovarian Cancer [J].

Christie, Elizabeth L. ;

Fereday, Sian ;

Doig, Ken ;

Pattnaik, Swetansu ;

Dawson, Sarah-Jane ;

Bowtell, David D. L. .

JOURNAL OF CLINICAL ONCOLOGY, 2017, 35 (12) :1274-1280

[7] Resistance to therapy caused by intragenic deletion in BRCA2 [J].

Edwards, Stacey L. ;

Brough, Rachel ;

Lord, Christopher J. ;

Natrajan, Rachael ;

Vatcheva, Radost ;

Levine, Douglas A. ;

Boyd, Jeff ;

Reis-Filho, Jorge S. ;

Ashworth, Alan .

NATURE, 2008, 451 (7182) :1111-U8

[8] Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy [J].

Farmer, H ;

McCabe, N ;

Lord, CJ ;

Tutt, ANJ ;

Johnson, DA ;

Richardson, TB ;

Santarosa, M ;

Dillon, KJ ;

Hickson, I ;

Knights, C ;

Martin, NMB ;

Jackson, SP ;

Smith, GCM ;

Ashworth, A .

NATURE, 2005, 434 (7035) :917-921

[9] Fast and accurate short read alignment with Burrows-Wheeler transform [J].

Li, Heng ;

Durbin, Richard .

BIOINFORMATICS, 2009, 25 (14) :1754-1760

[10] BRCAness revisited [J].

Lord, Christopher J. ;

Ashworth, Alan .

NATURE REVIEWS CANCER, 2016, 16 (02) :110-120

← 1 2 3 →