Molecular Profiling of Clear Cell Ovarian Cancers Identifying Potential Treatment Targets for Clinical Trials
Molecular Profiling of Clear Cell Ovarian Cancers Identifying Potential Treatment Targets for Clinical Trials
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DOI：
10.1097/igc.0000000000000677
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发表时间：
2016-05-01
影响因子：
4.8
通讯作者：
Voss, Andreas
中科院分区：
文献类型：
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作者：
Friedlander, Michael L.;Russell, Kenneth;Voss, Andreas
背景：晚期/复发性透明细胞卵巢癌（CCOCs）的特点是化疗反应低，预后差。在组织型特异性试验中，研究CCOC患者的新型/分子靶向治疗的兴趣越来越大。然而，CCOCs不是一个统一的实体，包括许多分子亚型，不太可能有一种单一的治疗方法适用于所有患者。本研究的目的是分析CCOCs的多平台分析面板的结果，以确定潜在的治疗targets.Patients和方法：肿瘤分析进行了521 CCOCs。将其分为纯CCOC（n = 422）和混合CCOC（n = 99）进行分析。测试包括一个组合的DNA测序（包括下一代测序），使用46个基因的面板，免疫组织化学，荧光或显色原位杂交，和RNA片段analysis.Results：最常见的结果是在PIK 3CA/Akt/mTOR通路，与61%的所有CCOCs显示在这些通路组件之一的分子改变。下一代测序显示50%的纯CCOC中存在PIK 3CA突变。在纯的和混合的CCOCs之间观察到激素受体表达的显著差异（ER为9% vs 34.7%，PR为13.45% vs 26.4%），cMET（24.1% vs 11.6%），PD-1肿瘤浸润淋巴细胞（48.1% vs 100%），PD-L1表达（7.4% vs 25%），TOPO 1（41% vs 27.1%），而下一代测序显示PIK 3CA突变频率存在显著差异，结论：这项大型研究证实了PIK 3CA/Akt/mTOR通路在CCOC中通常发生改变，并突出了纯CCOC和混合CCOC之间的显著差异。透明细胞卵巢癌是分子异质性的，有许多潜在的治疗靶点可以在临床试验中进行测试。
Background: Advanced stage/recurrent clear cell ovarian cancers (CCOCs) are characterized by a low response to chemotherapy and a poor prognosis. There is growing interest in investigating novel/molecular targeted therapies in patients with CCOC in histotype-specific trials. However, CCOCs are not a uniform entity and comprise a number of molecular subtypes and it is unlikely that a single approach to treatment will be appropriate for all patients. The aim of this study was to analyze the results of a multiplatform profiling panel in CCOCs to identify potential therapeutic targets.Patients and Methods: Tumor profiling was performed on 521 CCOCs. They were grouped into pure (n = 422) and mixed (n = 99) CCOC for analysis. Testing included a combination of DNA sequencing (including next-generation sequencing) using a 46-gene panel, immuno-histochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis.Results: The most common findings were in the PIK3CA/Akt/mTOR pathway, with 61% of all CCOCs showing a molecular alteration in one of these pathway components. Next-generation sequencing revealed PIK3CA mutations in 50% of pure CCOCs. Significant differences were observed between pure and mixed CCOCs with respect to hormone receptor expression (9% vs 34.7% for ER, 13.45 vs 26.4% for PR), cMET (24.1% vs 11.6%), PD-1 tumor infiltrating lymphocytes (48.1% vs 100%), expression of PD-L1 (7.4% vs 25%), and TOPO1 (41% vs 27.1%) on immunohistochemistry, whereas next-generation sequencing revealed significant differences in mutation frequency in PIK3CA (50% vs 18.5%), TP53 (18.1% vs 57.7%), KRAS (12.4% vs 3.7%), and cMET (1.9% vs 11.1%).Conclusions: This large study confirms that the PIK3CA/Akt/mTOR pathway is commonly altered in CCOCs, and highlights the significant differences between pure and mixed CCOCs. Clear cell ovarian cancers are molecularly heterogeneous and there are a number of potential therapeutic targets which could be tested in clinical trials.