Clear Cell Renal Cell Carcinoma Multiregion Sequencing (IRC 2014)

Overview

Multiregion exome sequencing (M-seq) cohort of 10 stage T2–T4 clear cell renal cell carcinoma (ccRCC) nephrectomies generating 79 tumor samples. Developed through the London Renal Cancer Consortium tissue protocol and the E-PREDICT translational trial (EUDRACT 2009-013381-54). Sequenced on Illumina HiSeq using Agilent SureSelect Human All Exon V4 (median ≥70× depth); 92.5% of candidate mutations validated by AmpliSeq ultra-deep amplicon sequencing (>400×) on Ion Torrent PGM. Raw exome data deposited at EGA (EGAS00001000667); gene-expression microarray at GEO (GSE53000).

Composition

  • 10 ccRCC primary tumors (CCRCC), stages T2 (n=2), T3 (n=7), T4 (n=1).
  • 79 tumor samples total: 8–20 macrodissected regions per nephrectomy, 8–12 retained for sequencing per case.
  • Additional metastatic samples for 4 cases (perinephric, chest-wall, lymph-node, renal-vein tumor thrombus).
  • Treatment context: 6 cases received preoperative everolimus; 1 case received sunitinib; 3 cases treatment-naive.

Assays / panels (linked)

Papers using this cohort

  • PMID:24487277 — Gerlinger et al. (2014): multiregion sequencing defining genomic architecture and ITH in ccRCC.

Notable findings derived from this cohort

  • 73–75% of driver aberrations (36/49 driver mutations; 57/76 driver SCNAs) were subclonal in all 10 ccRCCs; VHL inactivation and chromosome 3p loss were the only truncal events in every tumor PMID:24487277.
  • PBRM1 mutations were truncal in only 3 of 6 mutated tumors, qualifying it as a “facultative” trunk driver PMID:24487277.
  • Parallel evolution documented for PIK3CA, SETD2, BAP1, and the SWI/SNF complex across multiple tumors PMID:24487277.
  • Single-biopsy approaches underestimate driver-mutation prevalence: TP53 detected in 6% of individual biopsies vs 40% of cases; PI3K–mTOR pathway mutations in 28% vs 60% of cases PMID:24487277.
  • C>T transitions at CpG sites increased significantly on branch versus trunk mutations (q = 0.007), indicating shifting mutational processes during ccRCC evolution PMID:24487277.

Sources

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