Department of Pathology and Laboratory Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Department of Pathology and Laboratory Medicine, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Eur Urol Focus. 2018 Sep;4(5):740-748. doi: 10.1016/j.euf.2016.09.002. Epub 2016 Sep 22.
Two histologic subtypes are recognized for papillary renal cell carcinoma (PRCC). Studies have shown that the subtypes differ in characteristic genetic alterations and clinical behavior. Clinically, the subtypes are managed similarly.
To analyze the biological differences between the two PRCC histological subtypes, in order to further guide their clinical management.
DESIGN, SETTING, AND PARTICIPANTS: PRCC cohort consisting of 317 patients from the Cancer Genome Atlas database and our institution. Patients were stratified according to histologic criteria as type 1, type 2, or not otherwise specified (NOS). Gene and miRNA expression data for the cohort were examined via unsupervised and supervised clustering.
Significant molecular signatures for each subtype were used to unravel the implicated molecular pathways via bioinformatics analysis. Survival was compared between the subtypes. Newly discovered biomarkers were used to further stratify survival of patients in the NOS category.
Tumor genotyping revealed two distinct PRCC subtypes. The top molecular pathways enriched in PRCC1 were WNT, Hedgehog, and Notch signaling (p=0.001-0.01); highlighting an embryonic developmental theme to the pathogenesis of this subtype. PRCC2 showed enrichment in the mTOR, VEGF (p=7.49E-09) and HIF (p=7.63E-05) signaling pathways. Overall survival and disease-free survival significantly differed between the types. ABCC2 expression was identified as a significant prognostic biomarker for the NOS group in univariate (log rank p<0.0001; hazard ratio [HR] >11.63) and multivariate analysis (p=0.003; HR >2.12). ABCC2 expression and its effect on survival should be further validated at the protein level.
The classical PRCC types 1 and 2 have two distinct genotypes. We unraveled pathways that indicate that the two types could potentially respond differently to current therapies. We also identified biomarkers that stratify tumors within the PRCC NOS category into prognostic subgroups. Our findings highlight the need for molecular markers to accurately subtype PRCC and guide clinical management.
The two types of papillary renal cancer are treated similarly. We show that the two types have a different genetic makeup, and hence they should be considered two different tumors. There is a different biology underlying each tumor type that can potentially affect the way they respond to treatment. We uncovered genes that can be tested for to guide therapy in some problematic cases for which it hard to define the tumor type.
乳头状肾细胞癌（PRCC）有两种组织学亚型。研究表明，这两种亚型在特征性的遗传改变和临床行为上存在差异。临床上，这两种亚型的处理方式相似。
分析两种 PRCC 组织学亚型之间的生物学差异，以便进一步指导其临床管理。
设计、地点和参与者：PRCC 队列由癌症基因组图谱数据库和我们机构的 317 名患者组成。根据组织学标准，患者分为 1 型、2 型或未特指（NOS）。通过无监督和监督聚类检查队列的基因和 miRNA 表达数据。
使用每种亚型的显著分子特征通过生物信息学分析揭示所涉及的分子途径。比较亚型之间的生存情况。使用新发现的生物标志物进一步分层 NOS 类别患者的生存情况。
肿瘤基因分型显示出两种不同的 PRCC 亚型。在 PRCC1 中富集的顶级分子途径是 WNT、Hedgehog 和 Notch 信号通路（p=0.001-0.01）；强调了该亚型发病机制的胚胎发育主题。PRCC2 显示在 mTOR、VEGF（p=7.49E-09）和 HIF（p=7.63E-05）信号通路中富集。两种类型的总生存率和无病生存率有显著差异。ABCC2 表达被确定为 NOS 组单变量分析（对数秩 p<0.0001；风险比 [HR]>11.63）和多变量分析（p=0.003；HR>2.12）中的显著预后生物标志物。ABCC2 表达及其对生存的影响应在蛋白质水平上进一步验证。
经典的 PRCC 1 型和 2 型有两种不同的基因型。我们揭示了表明两种类型可能对当前治疗有不同反应的途径。我们还鉴定了可将 PRCC NOS 类别中的肿瘤分层为预后亚组的生物标志物。我们的发现强调了需要分子标记物来准确地对 PRCC 进行亚型分类并指导临床管理。
两种类型的乳头状肾癌的治疗方法相似。我们表明，这两种类型具有不同的遗传构成，因此它们应被视为两种不同的肿瘤。每种肿瘤类型都有不同的生物学基础，这可能会影响它们对治疗的反应方式。我们发现了一些可以测试的基因，以便在某些难以确定肿瘤类型的棘手情况下指导治疗。
