Renal Clear Cell Carcinoma (CCRCC)

Overview

Clear cell renal cell carcinoma (ccRCC) is the most common histologic subtype of renal cell carcinoma, arising from renal tubular epithelium and characterized by VHL loss and alterations in chromatin remodeling genes (BAP1, SETD2, PBRM1). It sits at OncoTree level 3 under the renal cell carcinoma (RCC) branch. First-line treatment options include immune checkpoint inhibitors (ICI), tyrosine kinase inhibitors (TKI), and combination regimens; biomarker-driven therapy selection is an active area of investigation.

Cohorts in the corpus

  • TCGA-KIRC: n=491 ccRCC samples; included in the 14-cohort meta-analysis (total n=3,621). PMID:22138691
  • IMmotion150: n=163 samples; IMmotion151: n=784 samples; JAVELIN Renal 101: n=701 samples — all included in the HiTME meta-cohort. PMID:22138691
  • WU-RCC (Washington University): independent validation cohort, n=193 with DNA-seq and RNA-seq (n=157 with bulk RNA-seq); spatial proteomics MxIF on n=34. PMID:22138691

Recurrent alterations

  • BAP1 — mutations associated with TKI non-response; enriched in fibrotic IE/M and F HiTME subtypes. PMID:22138691
  • SETD2 — mutations associated with TKI non-response in the WU-RCC validation cohort. PMID:22138691
  • PBRM1 — mutations enriched in TKI-high score group and in immune-enriched IE and IE/M HiTME subtypes. PMID:22138691
  • MTOR — activating mutations strongly associated with ICI and ICI+TKI non-response; 15 of 16 patients with MTOR-activating mutations were resistant to ICI regimens. PMID:22138691
  • KDM5C — mutational frequency varied across ICI and TKI score groups. PMID:22138691
  • NF2 — mutations more prevalent in the fibrotic F HiTME subtype. PMID:22138691
  • TCGA multi-platform characterization of 446 CCRCC primary nephrectomy specimens identified 19 significantly mutated genes (VHL, PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR, TP53 most significant), chromosome 3p loss in 91%, PI3K/AKT/mTOR pathway alteration in ~28%, and a metabolic Warburg shift correlating with worse survival PMID:23792563
  • Mouse scRNA-seq (147,045 cells) with conditional Vhl inactivation resolved isoform-specific roles of HIF1A and HIF2A in CCRCC initiation: HIF1A drives early glycolysis and papillary cell loss; HIF2A drives cortical proximal tubule dedifferentiation and proliferation, supporting early belzutifan use in VHL disease PMID:23797736
  • Multiregion exome sequencing (M-seq) of 10 ccRCCs found 73–75% of driver alterations were subclonal; only chromosome 3p loss and VHL inactivation were truncal across all tumors — single-biopsy approaches systematically underestimate driver-mutation prevalence PMID:24487277
  • TCGA multi-platform characterization of 66 ChRCC tumors identified CCRCC as a comparative cohort (417 tumors); ChRCC has a 3-fold lower mutation rate than ccRCC (~0.4/Mb), a non-Warburg mitochondrial metabolism phenotype, and distinct distal-nephron cell-of-origin — underscoring biological separation between the two RCC subtypes. PMID:25155756
  • URCC cohort (n=62, MSKCC) shows only 1/62 VHL mutations — stark contrast to ~75% in CCRCC; URCC NF2-loss and mTORC1-hyperactive subsets are mutually exclusive and both lack VHL alteration PMID:27713405.
  • PBRM1 loss-of-function was associated with clinical benefit from anti-PD-(L)1 therapy in metastatic CCRCC (9/11 CB vs 3/13 NCB, Fisher p=0.012; validated in 63-patient cohort, p=0.0071); PBRM1-LOF tumors showed upregulated JAK/STAT3 and hypoxia transcriptional programs PMID:29301960
  • MC3 pan-cancer mutation-calling project used KIRC (clear cell RCC) as a benchmark: running MutSig2CV and MuSiC2 on PASS variants yielded 10 SMGs each (TP53, PTEN, VHL, SETD2, PBRM1, BAP1, MTOR, and others); the unfiltered controlled MAF inflated these to 1,203 and 321 respectively, demonstrating the critical importance of the MC3 filtering strategy PMID:29596782

Subtypes

Five harmonized immune tumor microenvironment (HiTME) subtypes were defined by density-based clustering of functional gene expression signatures across 3,621 ccRCC samples from 14 cohorts: PMID:22138691

  • IE (immune-enriched, nonfibrotic): Highest ICI and TKI responder proportions; best prognosis.
  • IE/M (immune-enriched, myeloid immunosuppressive): Elevated ICI responder proportion but fibrotic features; worst overall survival in TCGA-KIRC.
  • F (fibrotic-myeloid immunosuppressive): Largest proportion of ICI non-responders; worst overall survival.
  • V (highly vascularized): High TKI responder proportion.
  • D (immune desert): Immunologically cold.

Therapeutic landscape

  • An integrated gradient-boosting decision-tree model classifies ccRCC patients as ICI/ICI-combo-preferred (56%), TKI-preferred (41%), or non-responsive (3%), validated across IMmotion151 and JAVELIN Renal 101 cohorts. PMID:22138691
  • ICI/ICI-combo-preferred patients had significantly longer PFS with atezolizumab+bevacizumab vs. sunitinib (IMmotion151, p=0.00005) and with avelumab+axitinib vs. sunitinib (JAVELIN, p=0.000007). PMID:22138691
  • MTOR-activating mutations and antigen presentation gene mutations may serve as molecular exclusion criteria for ICI therapy. PMID:22138691
  • ICI response model achieved ROC-AUC=0.77 (training) and ROC-AUC=0.78 (JAVELIN validation), outperforming all published single-biomarker signatures. PMID:22138691
  • TKI response model achieved ROC-AUC=0.74 on validation (n=822), outperforming JAVELIN Angio, IMmotion150 Angio, proliferation, and macrophage signatures. PMID:22138691

Sources

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