1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
Nature. 2015 May 28;521(7553):489-94. doi: 10.1038/nature14410.
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.
在过去的 30 年中，患有高级别浆液性卵巢癌（HGSC）的患者的总生存率几乎没有改善，标准治疗方法也没有超出铂类联合化疗。为了更好地了解临床表型的驱动因素，我们在此对 92 名原发性耐药、耐药、敏感和匹配获得性耐药疾病患者的肿瘤和种系 DNA 样本进行了全基因组测序。我们表明，基因断裂通常会使 HGSC 中的肿瘤抑制因子 RB1、NF1、RAD51B 和 PTEN 失活，并导致获得性化疗耐药。CCNE1 扩增在原发性耐药和难治性疾病中很常见。我们观察到与获得性耐药相关的几个分子事件，包括个别患者种系 BRCA1 或 BRCA2 突变的多次独立回复、BRCA1 启动子甲基化的丧失、分子亚型的改变以及与药物外排泵 MDR1 过表达相关的反复启动子融合。
