Proposing a molecular classification associated with hypercoagulation in ovarian clear cell carcinoma
Proposing a molecular classification associated with hypercoagulation in ovarian clear cell carcinoma
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DOI：
10.1016/j.ygyno.2021.08.009
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发表时间：
2021-10-30
影响因子：
4.7
通讯作者：
Enomoto，Takayuki
中科院分区：
文献类型：
--
作者：
Tamura，Ryo;Yoshihara，Kosuke;Enomoto，Takayuki
尽管卵巢透明细胞癌(CCC)血栓栓塞症的发生率较高，但其高凝状态的临床病理和生物学意义尚不清楚。材料和方法我们回顾分析了125例发现组和143例独立验证组的卵巢透明细胞癌治疗前D-二聚体水平、血栓栓子状态和临床结果。接下来，我们对93个CCCS进行了RNA测序，并将凝血相关基因图谱与2492个泛癌数据进行了比较。我们研究了基于凝血状态的CCC亚类分子特征的差异。结果在发现的数据集中，D-二聚体高于正常范围与较短的无进展和总生存期显著相关，与血栓栓塞状态无关。多因素分析显示，D-二聚体升高和临床分期是影响预后的独立因素。我们在验证集中证实了D-二聚体升高的预后意义。组织因子和IL6被认为是癌症诱导的高凝状态的关键因素，无论D-二聚体水平如何，在CCC中的表达都高于其他癌症。与没有D-二聚体升高的相比，CCC的各种致癌途径的活性更高。此外，系统聚类分析将57例D-二聚体升高的CCC分为免疫性热型和冷型。热性肿瘤以T细胞炎性表型丰富、炎症、上皮-间充质转化和血清C反应蛋白水平升高为特征，冷性肿瘤以细胞周期和MYC途径丰富为特征。结论CCC代表高凝状态，D-二聚体升高是预后因素。D-二聚体高CCC在炎症驱动途径(热瘤)和免疫抑制途径(冷瘤)中具有不同的分子特征。我们提出的分子分类的治疗意义值得进一步研究。
BackgroundAlthough ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear.Materials and methodsWe retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status.ResultsIn the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways.ConclusionsCCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation.