Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838

中文翻译：

---

透明细胞卵巢癌的分子亚类及其对疾病行为和结果的影响

目的：确定透明细胞卵巢癌 (CCOC) 的分子亚型并评估其对临床表现和结果的影响。实验设计：我们使用 163 个假定的 CCOC 驱动基因的靶向深度测序面板和对其中 211 个肿瘤的全转录组测序，对通过质量控制的 421 个原代 CCOC 进行了分析。确定了分子定义的亚组并测试其与临床特征和总体生存率的关联。结果：我们在 95% (401/421) 的 CCOC 肿瘤中检测到至少一个候选基因存在推定的体细胞驱动突变，包括 ARID1A（49% 的肿瘤）、PIK3CA（49%）、TERT（20%）和 TP53 (16%)。癌症驱动突变和 RNA 表达的聚类集中在 CCOC 的两个不同亚类上。第一个是 ARID1A 突变肿瘤，典型 CCOC 基因和铂耐药标志物表达丰富；第二个主要由具有 TP53 突变的肿瘤组成，并富集参与细胞外基质组织和间质分化的基因的表达。与 ARID1A 突变组相比，患有 TP53 突变肿瘤的女性更有可能患有晚期疾病，既往无子宫内膜异位症病史，且由于就诊时已处于晚期，生存率较差。在患有 ARID1A 突变肿瘤的女性中，一线铂类治疗的反应率有较低的趋势。结论：我们的研究表明，CCOC 由两个不同的分子亚类组成，具有不同的临床表现和结果，与传统和实验治疗反应性均具有潜在相关性。参见 Lheureux 的相关评论，第 17 页。4838