Whole-genome characterization of chemoresistant ovarian cancer
Whole-genome characterization of chemoresistant ovarian cancer
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DOI：
10.1038/nature14410
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发表时间：
2015-05-28
期刊：
影响因子：
64.8
通讯作者：
Bowtell, David D. L.
中科院分区：
文献类型：
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作者：
Patch, Ann-Marie;Christie, Elizabeth L.;Bowtell, David D. L.
在过去的30年里，高级别浆液性卵巢癌（HGSC）患者的总生存率几乎没有改善，标准治疗也没有超过铂类联合化疗。为了更好地了解临床表型的驱动因素，在这里，我们使用来自92名原发难治性，耐药，敏感和匹配的获得性耐药疾病患者的肿瘤和生殖系DNA样本的全基因组测序。我们发现，基因断裂通常使HGSC中的肿瘤抑制因子RB 1、NF 1、RAD 51 B和PTEN失活，并有助于获得性化疗耐药性。CCNE1扩增在原发耐药和难治性疾病中常见。我们观察到几个与获得性耐药相关的分子事件，包括个体患者生殖系BRCA 1或BRCA 2突变的多个独立逆转、BRCA 1启动子甲基化缺失、分子亚型改变以及与药物外排泵MDR 1过表达相关的复发性启动子融合。
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.