Unclassified Renal Cell Carcinoma — MSKCC (2016)

Overview

A single-institution prospective cohort of 62 high-grade primary renal cell carcinomas with unclassified histology (uRCC) assembled at MSKCC. All tumors were re-reviewed by three dedicated genitourinary pathologists applying WHO and ISUP consensus criteria; MiTF family translocation tumors were excluded by TFE3/TFEB IHC and FISH. The cohort represents the first in-depth integrated molecular characterization of uRCC, a heterogeneous RCC subgroup comprising 4–5% of all RCC and lacking a standard-of-care therapy. PMID:27713405

Composition

  • 62 high-grade primary uRCC tumors from MSKCC. PMID:27713405
  • Cancer type: unclassified renal cell carcinoma — a high-grade non-clear-cell RCC subgroup.
  • Clinicopathology: 58% locally advanced (≥pT3) at nephrectomy, 32% with regional lymph-node involvement; 42% (n=26) developed metastases and 35% (n=22) died of RCC during follow-up.
  • Four molecularly defined subsets: NF2 loss / Hippo–YAP dysregulation (26%), mTORC1-hyperactive (MTOR/TSC1/TSC2/PTEN mutations, 21%), FH deficiency (6%), and ALK translocation (2%), plus a chromatin/DNA-damage regulator group (21%). PMID:27713405

Assays / panels (linked)

Papers using this cohort

  • PMID:27713405 — Chen et al., Nat Genet 2016: Integrated molecular characterization of 62 uRCC tumors defining four molecular subsets with distinct drivers and clinical outcomes.

Notable findings derived from this cohort

  • 29 recurrently mutated genes identified; average 2.6 (range 0–8) somatic coding mutations per tumor. Most frequent: NF2 18%, SETD2 18%, BAP1 13%, KMT2C 10%, MTOR 8%; only 1/62 VHL mutation — sharply contrasting with ~75% in clear-cell RCC. PMID:27713405
  • NF2-loss subset (26%): Biallelic NF2 inactivation (mutation + 22q12 LOH) in 13/16 cases; concurrent SETD2 mutation in 44% of this subset (vs 9% in others, P=0.004); significant nuclear YAP/TAZ accumulation and depressed p-YAP; worst cancer-specific and progression-free survival by log-rank. PMID:27713405
  • mTORC1-hyperactive subset (21%): Mutually exclusive mutations in MTOR, TSC1, TSC2, or PTEN; MTOR L2427R recurred 3× and is functionally activating in 293T assays; 13/16 confirmed hyperactive by p-S6 / p-4EBP1 IHC; comparatively better clinical outcome. PMID:27713405
  • FH-deficient subset (6%): All 4 cases FH IHC-negative/2SC-positive; 3 confirmed HLRCC with germline FH mutations; T41 carries a somatic homozygous FH deletion — a novel non-germline mechanism. PMID:27713405
  • TPM3–ALK fusion (2%): T12 carries a TPM3–ALK fusion confirmed by IMPACT and ALK break-apart FISH — only the second adult RCC case reported with this fusion. PMID:27713405
  • Functional YAP dependency: shRNA knockdown of YAP1 in NF2-loss nccRCC cell lines reduces S- and G2/M-phase cells (P<0.001) and soft-agar colony formation. PMID:27713405

Sources

  • cBioPortal study ID: urcc_mskcc_2016
  • Chen et al., Nat Genet 2016 — DOI: 10.1038/ng.3587

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