Molecular Classification of Renal Cell Carcinoma and Its Implication in Future Clinical Practice

Abstract

Renal cell carcinoma (RCC) encompasses a wide spectrum of morphologically and molecularly distinct (>10) cancer subtypes originated from the kidney epithelium. Metastatic RCC (mRCC) is lethal and refractory to conventional chemotherapeutic agents. The incorporation of targeted therapies and immune checkpoint inhibitors into the current practice of mRCC has markedly improved the median overall survival of clear cell RCC (ccRCC) patients, the most common subtype, but not rare kidney cancer (RKC or non-ccRCC, nccRCC). Varied treatment response in mRCC patients is observed, which presents clinical challenges/opportunities at the modern mRCC therapeutic landscape consisting of 12 approved drugs representing 6 different effective mechanisms. Key contributing factors include inter- and intra-RCC heterogeneity. With the advances in pan-omics technologies, we now have a better understanding of the molecular pathobiology of individual RCC subtype. Here, we attempt to classify ccRCC based on contemporary molecular features with emphasis on their respective potential significance in clinical practice.

Keywords: Kidney cancer; biomarkers; genomics; metabolomics; molecular classification; precision medicine; proteomics; therapeutics; transcriptomics.

Fig.1

Somatic mutation landscape of ccRCC based on 10 genes that are selected for either prevalent mutations or shown prognostic/therapeutic significances. Top panel represents 220 metastatic ccRCC patients in the reported NGS cohort of RECORD3 [25], and bottom panel represents 418 ccRCC patients of all stages in the reported TCGA KIRC cohort [3]. MTORp denotes MTORC1 pathway.