类有机物
卵巢癌
DNA修复
同源重组
生物
计算生物学
DNA损伤
DNA
癌症研究
癌症
生物信息学
遗传学
作者
Sarah J. Hill,Brennan Decker,Emma A. Roberts,Neil S. Horowitz,Michael G. Muto,Michael J. Worley,Colleen M. Feltmate,Marisa R. Nucci,Elizabeth M. Swisher,Huy Nguyen,Chunyu Yang,Ryuji Morizane,Bose Kochupurakkal,T. Khanh,Panagiotis A. Konstantinopoulos,Joyce F. Liu,Joseph V. Bonventre,Ursula A. Matulonis,Geoffrey I. Shapiro,Ross S. Berkowitz,Christopher P. Crum,Alan D. D’Andrea
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2018-11-01
卷期号:8 (11): 1404-1421
被引量:322
标识
DOI:10.1158/2159-8290.cd-18-0474
摘要
Abstract Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic. Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404–21. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333
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