Non-Clear Cell Renal Cell Carcinoma — Genentech 2014

Overview

Integrated exome, RNA-seq, and SNP copy-number profiling of 167 primary non–clear cell renal cell carcinomas (nccRCC), generated by Durinck et al. (2014/2015) at Genentech in collaboration with the University of Texas Southwestern Kidney Cancer Program. Samples were sourced from UTSW. Raw data deposited at EGA under accession EGAS00001000926.

Composition

  • Cancer types: PRCC (67 papillary RCC), CHRCC (49 chromophobe RCC — 36 classic, 12 eosinophilic, 1 mixed), ROCY (35 renal oncocytomas), TRCC (6 translocation RCC), 8 unclassified, 2 sarcomatoid.
  • Exome profiling: 140 tumor-normal pairs + 5 tumor-only.
  • Targeted sequencing: 19 additional pRCCs with NuGEN Ovation Cancer Panel (344 genes).
  • RNA-seq: 159 tumors.
  • Copy-number profiling: Illumina HumanOmni2.5-8 SNP arrays.

Assays / panels (linked)

  • whole-exome-seq — Agilent SureSelect All Exon 50 Mb, Illumina HiSeq 2000, ~82× mean coverage; BWA alignment to GRCh37/hg19.
  • rna-seq — TruSeq, Illumina HiSeq 2000, ~68M paired-end reads/sample.
  • targeted-dna-seq — NuGEN Ovation Cancer Panel (344 genes) on 19 pRCC samples.
  • affymetrix-snp6 — Illumina HumanOmni2.5-8 arrays for copy-number profiling.
  • sanger-sequencing — orthogonal validation (96% indel validation rate).
  • fish — validation of amplifications and translocations.

Papers using this cohort

  • PMID:25401301 — Durinck et al. (2015), Nature Genetics. Spectrum of diverse genomic alterations define non–clear cell renal carcinoma subtypes.

Notable findings derived from this cohort

  • Ten significantly mutated genes in pRCC including MET (15%, with newly identified activating kinase-domain mutations), NF2, SLC5A3, SETD2, and CRTC1; six in chRCC (TP53, PTEN, FAAH2, PDHB, PDXDC1, ZNF765) PMID:25401301.
  • Novel transforming ACTG1-MITF fusion in pRCC induces HIF1A/MET/APEX1 targets; novel CLTC-TFEB fusion in an unclassified case reclassified as translocation RCC PMID:25401301.
  • Five-gene RNA-seq classifier (ASB1, GLYAT, PDZK1IP1, PLCG2, SDCBP2) separates pRCC, chRCC, and renal oncocytoma at 95.3% accuracy on a held-out 43-sample cohort PMID:25401301.
  • PRKAG2 and PDHB mutations in chRCC implicate AMPK/PDH metabolic deregulation; TSC1/TSC2/MTOR mutations nominate mTORC1 inhibitors in chRCC PMID:25401301.
  • BIRC7 overexpressed in 6/7 MiTF-family fusion/amplification tumors, proposed as a diagnostic and therapeutic target for the “MiTF-high” nccRCC subtype PMID:25401301.

Sources

  • EGA: EGAS00001000926.
  • cBioPortal study: nccrcc_genentech_2014.

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