Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression
Significance of BRCA2 and RB1 Co-loss in Aggressive Prostate Cancer Progression
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DOI：
10.1158/1078-0432.ccr-19-1570
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发表时间：
2020-04-01
影响因子：
11.5
通讯作者：
Kantoff, Philip W.
中科院分区：
文献类型：
--
作者：
Chakraborty, Goutam;Armenia, Joshua;Kantoff, Philip W.
目的：先前的测序研究显示，与DNA损伤反应（DDR）相关的基因改变在转移性去势抵抗性前列腺癌（mCRPC）男性中富集。BRCA 2是DDR和癌症易感基因，在侵袭性前列腺癌男性中经常缺失（纯合子和杂合子）。在这里，我们表明，前列腺癌患者谁失去了BRCA 2的拷贝经常失去一个拷贝的肿瘤抑制基因RB 1;重要的是，我们第一次证明，共同损失的两个基因在早期前列腺癌是足以诱导一个独特的生物学，这可能与预后较差。实验设计：我们前瞻性地研究了前列腺癌中BRCA 2和RB 1共同缺失的潜在分子机制和基因组后果。我们使用基于CRISPR-Cas9和RNAi的方法来消除前列腺癌细胞系中的这两个基因，并对它们进行体外研究和转录组学分析。我们开发了一种3色FISH检测方法，用于检测前列腺癌细胞和患者来源的mCRPC类器官中BRCA 2和RB 1的基因组缺失。结果：在人前列腺癌细胞系（LNCaP和LAPC 4）中，BRCA 2的缺失导致去势抵抗表型。BRCA 2-RB 1在人前列腺癌细胞中的共同缺失诱导上皮向间充质转化，这与侵袭性和更具侵袭性的疾病表型相关。重要的是，PARP抑制剂减弱细胞生长的人mCRPC衍生的类器官和人类CRPC细胞窝藏单拷贝loss的两个genes.Conclusions：我们的研究结果表明，早期识别这种侵略性的前列腺癌形式提供了潜在的改善结果与早期引入PARP的细胞因子为基础的治疗。
Purpose: Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC). BRCA2, a DDR and cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that patients with prostate cancer who have lost a copy of BRCA2 frequently lose a copy of tumor suppressor gene RB1; importantly, for the first time, we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis.Experimental Design: We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of BRCA2 and RB1 in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to in vitro studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of BRCA2 and RB1 in prostate cancer cells and patient-derived mCRPC organoids.Results: In human prostate cancer cell lines (LNCaP and LAPC4), loss of BRCA2 leads to the castration-resistant phenotype. Co-loss of BRCA2-RB1 in human prostate cancer cells induces an epithelial-to-mesenchymal transition, which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes.Conclusions: Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor-based therapy.