PALB2
奥拉帕尼
雷达51
PARP抑制剂
BRCA2蛋白
DNA修复
损失函数
癌症研究
同源重组
支票2
生殖系
种系突变
生物
微卫星不稳定性
前列腺癌
癌症
医学
突变
遗传学
聚ADP核糖聚合酶
表型
基因
等位基因
微卫星
聚合酶
作者
Suzanne Carreira,Núria Porta,Sara Arce‐Gallego,George Seed,Alba Llop‐Guevara,Diletta Bianchini,Pasquale Rescigno,Alec Paschalis,Cláudia Bertan,Chloe Baker,Jane Goodall,Susana Miranda,Ruth Riisnaes,Ines Figueiredo,Ana Ferreira,Rita Pereira,Mateus Crespo,Bora Gürel,Daniel Nava Rodrigues,Stephen J. Pettitt
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-05-27
卷期号:11 (11): 2812-2827
被引量:135
标识
DOI:10.1158/2159-8290.cd-21-0007
摘要
Abstract PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B phase II clinical trial samples, evaluating whole-exome and low-pass whole-genome sequencing and IHC and IF assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA2 deletion. Biallelic, but not monoallelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by IHC was associated with a better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alterations while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM IHC expression associated with clinical benefit. Significance: Not all APCs with DNA repair defects derive similar benefit from PARP inhibition. Most benefit was seen among patients with BRCA2 homozygous deletions, biallelic loss of PALB2, and loss of ATM protein. Loss of RAD51 foci, evaluating homologous recombination repair function, was found primarily in tumors with biallelic BRCA1/2 and PALB2 alterations. This article is highlighted in the In This Issue feature, p. 2659
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