Esophageal Squamous Cell Carcinoma (UCLA 2014)

Overview

Genomic characterization cohort of 139 paired ESCC germline/tumor samples using whole-exome or targeted deep sequencing, plus somatic copy-number analysis of over 184 ESCC cases. Discovery cohort (n=20) used whole-exome sequencing (mean 79×); frequency cohort (n=119 + 10 cell lines) used targeted deep sequencing of discovery-mutated genes plus 277 cancer-relevant genes (mean 111×). Additional SCNV analysis from SNP arrays (Affymetrix 250K) and array-CGH (44K Agilent) across 184 ESCC samples. FISH validation of FGFR1 amplification in 53 additional tumors; IHC validation on TMAs. Samples collected at CAMS and Linxian Cancer Hospital; sequence data deposited at SRA (SRP033394).

Composition

• 139 paired ESCC tumor/germline cases (ESCC); exclusively from high-incidence Chinese centers.
• 20-case discovery cohort (WES) + 119-case + 10 cell-line frequency cohort (targeted).
• SCNV analysis on 184 primary ESCC samples; FISH on additional 53 tumors.
• Only tumors with >70% malignant cells included.

Assays / panels (linked)

• Whole-exome sequencing — discovery cohort, mean 79×
• Targeted DNA sequencing — frequency cohort, mean 111×
• RNA-seq — 4 discovery-cohort tumors
• Affymetrix 250K SNP array — SCNV analysis
• Array-CGH — SCNV analysis
• FISH — FGFR1 amplification validation
• MutSigCV — significantly mutated gene calling

Papers using this cohort

• PMID:24686850 — Lin et al. (2014): genomic and molecular characterization of ESCC identifying novel drivers and XPO1 as therapeutic target.

Notable findings derived from this cohort

• 13 significantly mutated genes identified by MutSigCV (FDR q < 0.2); novel ESCC drivers include FAT1, FAT2, ZNF750, and KMT2D alongside established drivers TP53, PIK3CA, and NOTCH1 PMID:24686850.
• APOBEC3B implicated as the major mutagen via trinucleotide signature analysis; mRNA up-regulated in ESCC tumors PMID:24686850.
• FGFR1 newly identified as recurrently amplified: FISH confirmed amplification in 11/53 additional ESCCs; IHC showed protein up-regulation in 17.3% of tumors PMID:24686850.
• XPO1 carries a recurrent D624G missense mutation; protein and mRNA overexpressed in ESCC; selinexor (KPT-330) induced apoptosis and growth arrest in ESCC cell lines PMID:24686850.
• CCND1 at 11q13.2 was the most frequent focal amplification; additional amplification peaks involved EGFR, MYC, and KRAS; CDKN2A was focally deleted PMID:24686850.
• RTK-MAPK-PI3K, cell-cycle, and epigenetic pathways were significantly and frequently dysregulated; 31 candidate actionable alterations identified PMID:24686850.

Sources

• PMID:24686850

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