BACKGROUND Clear cell renal cell carcinoma (ccRCC) is a particularly challenging tumor type because of its extensive phenotypic variability as well as intra-tumoral heterogeneity (ITH). Clinically, this complexity has been reduced to a handful of pathological variables such as stage, grade and necrosis, but these variables fail to capture the breadth of the disease. How different phenotypes affect patient prognosis and influence therapeutic response is poorly understood. Extensive ITH illustrates remarkable plasticity, providing a framework to study tumor evolution. While multiregional genomic analyses have shown evolution from an ancient clone that acquires metastatic competency over time, these studies have been conducted agnostic to morphological cues and phenotypic plasticity. METHODS We established a systematic ontology of ccRCC phenotypic variability by developing a multi-scale framework along three fundamental axes: tumor architecture, cytology and the microenvironment. We defined 33 parameters, which we comprehensively evaluated in 549 consecutive ccRCCs retrospectively. We systematically evaluated the impact of each parameter on patient outcomes, and assessed their contribution through multivariate analyses. We measured therapeutic impact in the context of anti-angiogenic therapies. We applied dimensionality reduction by t-distributed stochastic neighbor embedding (t-SNE) algorithms to tumor architectures for the study of tumor evolution superimposing tumor size and grade vectors. Evolutionary models were refined through empirical analyses of directed evolution of tumor intravascular extensions, and metastatic competency (as determined by tumor reconstitution in a heterologous host). FINDINGS We discovered several novel ccRCC phenotypes, developed an integrated taxonomy, and identified features that improve current prognostic models. We identified a subset of ccRCCs refractory to anti-angiogenic therapies. We developed a model of tumor evolution, which revealed converging evolutionary trajectories into an aggressive type. INTERPRETATION This work serves as a paradigm for deconvoluting tumor complexity and illustrates how morphological analyses can improve our understanding of ccRCC pleiotropy. We identified several subtypes associated with aggressive biology, and differential response to targeted therapies. By analyzing patterns of spatial and temporal co-occurrence, intravascular tumor extensions and metastatic competency, we were able to identify distinct trajectories of convergent phenotypic evolution.

中文翻译：

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本体分析表明，临床上重要的透明细胞肾细胞癌亚型具有逐渐演变成侵略性的进化轨迹。

背景技术透明细胞肾细胞癌（ccRCC）由于其广泛的表型变异性以及肿瘤内异质性（ITH）而成为特别具有挑战性的肿瘤类型。在临床上，这种复杂性已减少到少数病理变量，例如阶段，等级和坏死，但这些变量无法捕获疾病的广度。人们对不同的表型如何影响患者的预后以及如何影响治疗反应的了解甚少。广泛的ITH显示出显着的可塑性，为研究肿瘤的发展提供了框架。尽管多区域基因组分析显示了随着时间的流逝获得转移能力的古老克隆的进化，但这些研究却与形态学线索和表型可塑性无关。方法我们通过沿三个基本轴开发多尺度框架来建立ccRCC表型变异性的系统本体论：肿瘤结构，细胞学和微环境。我们定义了33个参数，我们分别对549个连续ccRCC进行了综合评估。我们系统地评估了每个参数对患者预后的影响，并通过多元分析评估了它们的贡献。我们在抗血管生成疗法的背景下测量了治疗效果。我们将通过t分布随机邻居嵌入（t-SNE）算法进行的降维应用于肿瘤架构，以研究叠加了肿瘤大小和等级向量的肿瘤进化。通过对肿瘤血管内延伸的定向进化的经验分析，完善了进化模型，和转移能力（由异源宿主中的肿瘤重建确定）。结果我们发现了几种新颖的ccRCC表型，建立了一个综合分类法，并确定了可改善当前预后模型的特征。我们确定了抗血管生成疗法难治的ccRCCs的子集。我们开发了一种肿瘤进化模型，该模型揭示了进化轨迹趋于侵略性的趋势。解释这项工作是反卷积肿瘤复杂性的范例，并说明了形态学分析如何改善我们对ccRCC多效性的理解。我们确定了几种与侵略性生物学相关的亚型，以及对靶向疗法的不同反应。通过分析时空共生，血管内肿瘤扩展和转移能力的模式，