HCC INSERM France 2015 (Schulze et al.)
Overview
Multi-institutional European whole-exome sequencing cohort of 243 surgically resected hepatocellular carcinomas (HCC) with matched non-tumor liver, assembled by Schulze, Letouzé, Zucman-Rossi and colleagues at INSERM (Paris-Créteil, Bordeaux), with additional cases from Milan (n=41) and Barcelona (n=9). Published in Nature Genetics 2015 (PMID:25822088). Raw data deposited in EGA (EGAS00001000217, EGAS00001000679, EGAS00001001002) and ICGC data portal (release 18, 10 December 2014).
Composition
- N = 243 surgically resected liver tumors (193 France, 41 Italy, 9 Spain); matched non-tumor liver for all.
- Cancer type: HCC.
- Fibrosis: F4 cirrhosis n=118; F2–F3 n=46; F0–F1 non-fibrotic n=79.
- Risk factors: alcohol 41%, HCV 26%, NASH/metabolic syndrome 18%, HBV 14%, hemochromatosis 7%, unknown etiology 11%.
- Tumor progression stages: 7 dysplastic macronodules, 7 early HCC, 17 small-progressed HCC, 58 classic HCC, 29 poor-prognosis HCC.
Assays / panels (linked)
- whole-exome-seq — Agilent SureSelect v2/v3/v4/v5+UTRs on Illumina HiSeq 2000 (paired-end 75 bp); mean depth 72× (~92.6% targeted bases at ≥10×).
- sanger-sequencing — validation of 11 genes in 155 tumors; 88% sensitivity (95% CI 82–92%), 99% specificity.
- mutational-signatures — Wellcome Trust Sanger Institute NMF framework; identified 8 signatures including novel signatures 23 and 24.
- mutsig — MutSigCV for significantly mutated gene discovery.
- oncotator — variant annotation (alongside Alamut).
Papers using this cohort
- PMID:25822088 — Schulze et al., Nature Genetics 2015: whole-exome sequencing of 243 HCC; primary discovery study for this cohort.
Notable findings derived from this cohort
- 14 significantly mutated genes (MutSigCV q < 0.05): TP53, CTNNB1, AXIN1, ALB, ARID1A, ARID2, ACVR2A, NFE2L2, RPS6KA3, KEAP1, RPL22, CDKN2A, CDKN1A, and RB1. PMID:25822088
- Two novel mutational signatures discovered (23 and 24); signature 24 (high C>A rate) implicates aflatoxin B1 exposure and co-segregates with TP53 R249S in HBV-infected patients of sub-Saharan African origin. PMID:25822088
- TERT promoter mutation is the earliest genomic event during cirrhosis-to-HCC progression; CDKN2A inactivation and FGF3/FGF4/FGF19/CCND1 amplification independently predict poor 60-month overall survival in R0-resected patients. PMID:25822088
- 161 putative driver genes spanning 11 recurrently altered pathways; 28% of HCC harbored at least one alteration potentially targetable by an FDA-approved drug; 86% by a drug in phase I–III trials. PMID:25822088
- Etiology-specific mutation enrichments: alcohol-related HCC enriched for CTNNB1, TERT, CDKN2A, SMARCA2, HGF; HBV-related HCC enriched for TP53 mutation. PMID:25822088
Sources
- cBioPortal study:
hcc_inserm_fr_2015 - EGA: EGAS00001000217, EGAS00001000679, EGAS00001001002
- ICGC data portal release 18 (10 December 2014)
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