Clemson University Department of Genetics & Biochemistry, Clemson, SC, USA.
Molecular Oncology, Department of Medicine, Siteman Cancer Center, Washington University, St Louis, MO, USA.
Sci Rep. 2019 Feb 27;9(1):2899. doi: 10.1038/s41598-019-39875-y.
Renal cell carcinoma (RCC) subtypes are characterized by distinct molecular profiles. Using RNA expression profiles from 1,009 RCC samples, we constructed a condition-annotated gene coexpression network (GCN). The RCC GCN contains binary gene coexpression relationships (edges) specific to conditions including RCC subtype and tumor stage. As an application of this resource, we discovered RCC GCN edges and modules that were associated with genetic lesions in known RCC driver genes, including VHL, a common initiating clear cell RCC (ccRCC) genetic lesion, and PBRM1 and BAP1 which are early genetic lesions in the Braided Cancer River Model (BCRM). Since ccRCC tumors with PBRM1 mutations respond to targeted therapy differently than tumors with BAP1 mutations, we focused on ccRCC-specific edges associated with tumors that exhibit alternate mutation profiles: VHL-PBRM1 or VHL-BAP1. We found specific blends molecular functions associated with these two mutation paths. Despite these mutation-associated edges having unique genes, they were enriched for the same immunological functions suggesting a convergent functional role for alternate gene sets consistent with the BCRM. The condition annotated RCC GCN described herein is a novel data mining resource for the assignment of polygenic biomarkers and their relationships to RCC tumors with specific molecular and mutational profiles.
肾细胞癌 (RCC) 亚型的特征是具有不同的分子特征。我们使用来自 1009 个 RCC 样本的 RNA 表达谱，构建了一个条件注释的基因共表达网络 (GCN)。RCC GCN 包含特定于条件的二进制基因共表达关系 (边)，包括 RCC 亚型和肿瘤分期。作为该资源的应用，我们发现了与已知 RCC 驱动基因中的遗传病变相关的 RCC GCN 边和模块，包括 VHL，这是常见的起始透明细胞 RCC (ccRCC) 遗传病变，以及 PBRM1 和 BAP1，它们是 Braided Cancer River Model (BCRM) 中的早期遗传病变。由于 PBRM1 突变的 ccRCC 肿瘤对靶向治疗的反应与 BAP1 突变的肿瘤不同，因此我们专注于与表现出替代突变谱的肿瘤相关的 ccRCC 特异性边：VHL-PBRM1 或 VHL-BAP1。我们发现与这两种突变途径相关的特定分子功能混合。尽管这些与突变相关的边具有独特的基因，但它们富含相同的免疫功能，这表明替代基因集具有一致的功能作用，与 BCRM 一致。本文描述的条件注释的 RCC GCN 是一个新的数据挖掘资源，用于分配多基因生物标志物及其与具有特定分子和突变特征的 RCC 肿瘤的关系。
