Unclassified Renal Cell Carcinoma (URCC)

Overview

Unclassified renal cell carcinoma (URCC) is an OncoTree child of Renal Non-Clear Cell Carcinoma (NCCRCC) and represents high-grade primary renal tumors that cannot be assigned to any established RCC subtype after rigorous pathologic review. URCC comprises approximately 4–5% of all RCC. It lacks a standard of care and is molecularly heterogeneous. A landmark MSKCC molecular characterization study of 62 high-grade primary uRCCs using MSK-IMPACT, RNA-seq, OncoScan SNP arrays, FISH, and IHC defined four molecularly distinct subsets covering ~76% of cases: NF2 loss (26%), mTORC1-hyperactive (21%), FH-deficient (6%), and ALK translocation (2%), with a chromatin/DNA-damage regulator group (21%) PMID:27713405.

Cohorts in the corpus

  • urcc_mskcc_2016 — 62 high-grade primary uRCC tumors from MSKCC, re-reviewed by three genitourinary pathologists; all profiled with the 230-gene MSK-IMPACT panel (avg 348x coverage), with RNA-seq (n=7), OncoScan SNP arrays (n=15/16 NF2-loss cases), FISH, and IHC PMID:27713405.

Recurrent alterations

  • NF2 — mutated in 18% (11/62); biallelic inactivation by mutation plus 22q12 LOH in 13/16 (81%) of the NF2-loss subset; drives Hippo–YAP pathway dysregulation with nuclear YAP/TAZ accumulation; shYAP1 knockdown reverses proliferation phenotype in NF2-loss nccRCC lines (ACHN, LB996-RCC) PMID:27713405.
  • SETD2 — 18% overall, but 44% within the NF2-loss subset (Fisher P=0.004); complete loss of H3K36me3 mark co-occurs with mutation PMID:27713405.
  • BAP1 — 13% PMID:27713405.
  • KMT2C, KMT2D, KMT2A — chromatin modulators recurrently mutated (~16% combined across KMT2 family) PMID:27713405.
  • MTOR — 8% missense; recurrent L2427R (3 cases) functionally activating in 293T co-transfection assays; defines the mTORC1-hyperactive subset together with TSC1, TSC2, and PTEN PMID:27713405.
  • TSC1, TSC2, PTEN — together with MTOR define the mTORC1-hyperactive subset (n=13, 21%); mutually exclusive across the 16-case set; 7 TSC1/TSC2-mutated tumors show maximal p-4EBP1 (H-score=300) PMID:27713405.
  • FH — defines the FH-deficient subset (n=4, 6%); three confirmed HLRCC cases with germline FH mutations; one somatic homozygous FH deletion (T41) represents a novel non-germline mechanism PMID:27713405.
  • ALK and TPM3 — TPM3–ALK fusion in T12 (2%); confirmed by ALK break-apart FISH; second adult RCC case with this fusion PMID:27713405.
  • VHL — only 1/62 mutations (T08); absence of VHL alteration despite frequent 3p loss distinguishes uRCC from CCRCC PMID:27713405.
  • YAP1 and WWTR1 (TAZ) — not mutated but nuclear accumulation marks the NF2-loss subset PMID:27713405.
  • TP53, CHEK2, BRCA2 — DNA-damage-response mutations in 5 of the chromatin/DNA-damage group cases PMID:27713405.
  • MET H1094Y and BRAF Y472C — pathogenic mutations in single cases (T62, T69) suggesting candidate therapeutic targets PMID:27713405.

Subtypes

  • NF2-loss (26%, n=16): Defined by NF2 mutation and/or 22q12 loss; biallelic inactivation in 81%; Hippo–YAP dysregulation confirmed by RNA-seq GSEA; co-occurrence with SETD2 mutation (44%) causes H3K36me3 loss. Associated with worst cancer-specific and progression-free survival PMID:27713405.
  • mTORC1-hyperactive (21%, n=13): Mutually exclusive MTOR/TSC1/TSC2/PTEN mutations in 16 cases; 13/16 confirmed by p-S6 and p-4EBP1 IHC. Comparatively better clinical course; biologically similar to mTOR-altered CCRCC where mTOR inhibitors have shown benefit PMID:27713405.
  • FH-deficient (6%, n=4): FH IHC-negative and 2SC-positive; three HLRCC cases plus one case with somatic homozygous FH deletion. Associated with worst survival PMID:27713405.
  • ALK-translocation (2%, n=1): TPM3–ALK fusion; confirms uRCC as an emerging RCC entity with ALK rearrangement PMID:27713405.
  • Chromatin/DNA-damage regulator (21%, n=13): Eight cases with SETD2, BAP1, KMT2A/C/D, PBRM1 mutations; 5 with TP53, CHEK2, BRCA2 mutations; intermediate outcome PMID:27713405.
  • Other (24%, n=15): No recurrent molecular feature identified PMID:27713405.

Therapeutic landscape

  • mTORC1-hyperactive uRCC (21%): biological rationale for mTOR inhibitor use (MTOR/TSC1/TSC2/PTEN alterations analogous to ccRCC long-term mTOR-inhibitor responders) PMID:27713405.
  • NF2-loss uRCC: candidate for YAP-pathway inhibitors (e.g., verteporfin); concurrent SETD2 mutation with H3K36me3 loss supports WEE1-inhibitor synthetic-lethality hypothesis PMID:27713405.
  • FH-deficient cases: genetic counselling for HLRCC recommended PMID:27713405.
  • ALK-translocation case (TPM3–ALK): candidate for ALK inhibition PMID:27713405.

Sources

  • PMID:27713405 — Chen et al., first in-depth molecular characterization of 62 MSKCC high-grade uRCCs via MSK-IMPACT; defines four molecularly distinct subsets.

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