ICGC Cholangiocarcinoma Multi-Omic Cohort 2017 (Jusakul et al.)

Overview

The ICGC CCA cohort is the largest integrated multi-omic survey of cholangiocarcinoma to date, assembled by the International Cancer Genome Consortium across 10 countries. Jusakul et al. profiled 489 cholangiocarcinomas from patients spanning fluke-positive (132 Opisthorchis viverrini, 1 Clonorchis sinensis) and fluke-negative etiologies (including HBV/HCV-positive and PSC-positive subsets). Tumors were collected prior to any systemic therapy and staged using AJCC 7th edition criteria. The primary goal was to identify etiology-driven molecular subtypes by integrating genomic, epigenomic, and transcriptomic data, and to nominate new therapeutic targets based on subtype-specific vulnerabilities PMID:28667006.

Composition

• Total: 489 cholangiocarcinomas from 10 countries; 133 Fluke-Positive (OV/CS), 356 Fluke-Negative; 39 HBV/HCV-positive; 5 PSC-positive; all untreated.
• Anatomical breakdown: intrahepatic (IHCH), perihilar (PHCH), and distal extrahepatic (EHCH); survival data available for 459 samples.
• Platform breakdown: whole-genome sequencing (WGS) n=71 tumor/normal pairs (avg 64.2× depth, Illumina HiSeq X10/2500/2000); whole-exome sequencing (WES) n=200 (previously published); targeted sequencing of 404 genes n=188 (SureSelect XT2, HiSeq 4000); SNP arrays (HumanOmniExpress) n=175; Illumina 450K methylation BeadChip n=138; HumanHT-12 Expression BeadChip n=118 PMID:28667006.
• Integrative subset: 94 samples with all four data types used for iClusterPlus clustering; expanded to 121 samples for reanalysis (90% cluster-prediction accuracy).
• Validation cohort: newly classified samples plus a published 38-sample US TCGA CCA series for survival reproducibility PMID:28667006.

Assays / panels (linked)

• whole-genome-seq
• whole-exome-seq
• targeted-dna-seq
• 450k-methylation-array
• microarray-gene-expression
• icluster
• mutational-signatures
• ascat
• crest
• mutsig
• firefly
• estimate

Papers using this cohort

• PMID:28667006 — Jusakul et al. 2017; first comprehensive multi-omic landscape of 489 CCAs defining four etiology-driven molecular subtypes.

Notable findings derived from this cohort

• Four integrative molecular subtypes (Clusters 1–4) defined by iClusterPlus: Clusters 1–2 enriched in TP53 mutations and ERBB2 amplifications (Fluke-Positive); Cluster 3 with highest CNA burden and immune-checkpoint upregulation (PDCD1, PDCD1LG2); Cluster 4 with IDH1/IDH2 mutations, BAP1 inactivation, and FGFR2 rearrangements PMID:28667006.
• Four newly nominated CCA driver genes: RASA1 (4.1% inactivating, shRNA knockdown enhances migration/invasion), STK11 (5% inactivating), MAP2K4 (homozygous deletions + 2.2% mutations), and SF3B1 (4.6% at codons 625/700) PMID:28667006.
• First FGFR3-TACC3 fusion reported in CCA; FGFR2 3′UTR truncating rearrangements identified as a new mechanism of FGFR2 upregulation beyond canonical in-frame fusions PMID:28667006.
• ERBB2 amplification enriched in Fluke-Positive CCAs (10.4% vs 2.7%, p<0.01; avg 14 copies, FISH-validated); activating ERBB2 point mutations in 2% of cases; nominates anti-HER2 therapy in Clusters 1–2 PMID:28667006.
• Two distinct DNA-methylation subgroups: Cluster 1 CpG-island hypermethylation (TET1 downregulated, EZH2 upregulated) and Cluster 4 CpG-shore hypermethylation (IDH1/2-driven or BAP1-associated) PMID:28667006.
• Clusters 3 and 4 carry significantly better overall survival than Clusters 1–2 (log-rank p<0.001), independent of fluke status, anatomy, and stage; reproduced in an independent validation cohort PMID:28667006.
• Ten COSMIC mutational signatures detected; APOBEC enriched in Fluke-Positive tumors (p<0.001); Signature 1 (CpG>TpG deamination) elevated in Cluster 1; L1 retrotransposition from TTC28 intron-1 in 28.2% of WGS tumors PMID:28667006.
• FIREFLY method applied to 70 WGS samples identified four gene sets enriched for promoter mutations that alter TF binding and produce concordant transcriptional dysregulation, predominantly affecting PRC2/H3K27me3 pathways in Cluster 1 PMID:28667006.

Sources

• Jusakul A, Cutcutache I, Yong CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Cell. 2017;32(4):516-527.e8. PMID:28667006

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