Gargiuli Chiara, Sepe Pierangela, Tessari Anna, Sheetz Tyler, Colecchia Maurizio, de Braud Filippo Guglielmo Maria, Procopio Giuseppe, Sensi Marialuisa, Verzoni Elena, Dugo Matteo
Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Cancers (Basel). 2021 Jun 10;13(12):2903. doi: 10.3390/cancers13122903.
Collecting duct carcinoma (CDC) is a rare and highly aggressive kidney cancer subtype with poor prognosis and no standard treatments. To date, only a few studies have examined the transcriptomic portrait of CDC. Through integration of multiple datasets, we compared CDC to normal tissue, upper-tract urothelial carcinomas, and other renal cancers, including clear cell, papillary, and chromophobe histologies. Association between CDC gene expression signatures and in vitro drug sensitivity data was evaluated using the Cancer Therapeutic Response Portal, Genomics of Drug Sensitivity in Cancer datasets, and connectivity map. We identified a CDC-specific gene signature that predicted in vitro sensitivity to different targeted agents and was associated to worse outcome in clear cell renal cell carcinoma. We showed that CDC are transcriptionally related to the principal cells of the collecting ducts providing evidence that this tumor originates from this normal kidney cell type. Finally, we proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Our findings elucidate the molecular features of CDC providing novel biological and clinical insights. The identification of distinct CDC subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches.
集合管癌(CDC)是一种罕见且侵袭性很强的肾癌亚型,预后较差且没有标准治疗方法。迄今为止,仅有少数研究对CDC的转录组特征进行了检测。通过整合多个数据集,我们将CDC与正常组织、上尿路尿路上皮癌以及其他肾癌(包括透明细胞癌、乳头状癌和嫌色细胞癌组织学类型)进行了比较。利用癌症治疗反应门户、癌症药物敏感性基因组学数据集和连通性图谱,评估了CDC基因表达特征与体外药物敏感性数据之间的关联。我们鉴定出一种CDC特异性基因特征,该特征可预测对不同靶向药物的体外敏感性,并与透明细胞肾细胞癌的较差预后相关。我们表明,CDC在转录水平上与集合管的主细胞相关,这为该肿瘤起源于这种正常肾细胞类型提供了证据。最后,我们证明CDC是一种分子异质性疾病,由至少两种通过细胞信号传导、代谢和免疫相关改变区分的亚型组成。我们的研究结果阐明了CDC的分子特征,提供了新的生物学和临床见解。不同CDC亚型及其转录组特征的鉴定为患者分层和替代治疗方法提供了理论依据。