Esophageal Squamous Cell Carcinoma (ESCC)

Overview

Esophageal Squamous Cell Carcinoma (ESCC) is the predominant histologic subtype of esophageal cancer globally, with highest incidence in China and other high-risk geographic corridors. In OncoTree it is classified under Esophagogastric Cancer (parent: STOMACH). The canonical genomic landscape includes frequent TP53, PIK3CA, NOTCH1, NFE2L2, CDKN2A, and RB1 alterations, as well as novel drivers FAT1, FAT2, ZNF750, KMT2D, and XPO1.

Cohorts in the corpus

  • 139 paired ESCC tumor/germline samples (20 WES + 119 targeted deep sequencing); SCNV analysis of 184 ESCC cases — Chinese CAMS/Linxian cohort — PMID:24686850
  • 18 case–control oral microbiome studies (1,191 cases / 1,403 controls) — systematic review; no primary ESCC genomic cohort in this paper PMID:24670651

Recurrent alterations

  • WES + targeted sequencing of 139 ESCCs identified 13 significantly mutated genes (MutSigCV q < 0.2): TP53, PIK3CA, NOTCH1 (confirmed), plus novel drivers FAT1, FAT2, FAT3 (mutually exclusive truncating mutations), ZNF750, KMT2D, XPO1 (D624G), FBXW7, PBRM1, ARID2, KDM6A, KMT2C; mean 15 non-silent somatic mutations per case PMID:24686850
  • APOBEC3B implicated as the dominant mutational mechanism in ESCC via trinucleotide signature analysis PMID:24686850
  • Recurrent focal amplifications: CCND1 (11q13.2, most frequent), FGFR1 (amplified in 11/53 ESCC by FISH; overexpressed by IHC in 17.3%), EGFR, MYC, KRAS; recurrent focal deletion: CDKN2A PMID:24686850
  • Significantly altered pathways: MAPK (P = 0.0005), PI3K (P = 0.0004), JAK-STAT3 (P = 0.0006), G1-S cell cycle (P = 1.63E-05), and epigenetic modification (P = 0.0013) PMID:24686850
  • Oral microbial signatures (Prevotella, Porphyromonas gingivalis, Fusobacterium nucleatum enrichment; Neisseria, Lautropia, Corynebacterium depletion) associate with ESCC risk; pooled OR 9.50 (95% CI 5.89–15.29) from two-study meta-analysis PMID:24670651
  • TCGA profiling of 90 esophageal squamous cell carcinomas defined three molecular subtypes: ESCC1 (NRF2-pathway/classical squamous, NFE2L2/KEAP1/CUL3 alterations, SOX2/TP63 amplification, VGLL4 deletion), ESCC2 (NOTCH/PI3K/immune-infiltrated, NOTCH1/ZNF750 mutations, KMT2D/KDM6A alterations, CDK6 amplification), ESCC3 (PI3K-activated, SMARCA4/KMT2D mutant, US/Canada only); ESCC resembles head/neck and lung squamous tumors; no HPV aetiologic role; Vietnamese ESCC enriched for NFE2L2 mutations (24% vs 6%) PMID:28052061
  • Pan-cancer aneuploidy study placed ESCC in the squamous arm-level cluster (chr_3p loss + chr_3q gain) alongside HPV+ and HPV− HNSC, CESC, and LUSC; the squamous chr_3 signature was most prominent in LUSC, ESCC, and HPV-negative HNSC PMID:29622463

Subtypes

  • Squamous cell carcinoma is distinguished from esophageal adenocarcinoma (ESCA) by distinct genomic drivers (APOBEC3B mutagenesis, ZNF750 loss) and different oral microbial enrichment patterns PMID:24670651, PMID:24686850

Therapeutic landscape

  • Selinexor (KPT-330, XPO1 inhibitor) induced apoptosis and growth arrest in ESCC cell lines at submicromolar concentrations; XPO1 D624G mutation and protein overexpression correlate with larger tumor size PMID:24686850
  • FGFR1 amplification (~6–17% of ESCC) proposed as a candidate biomarker for FGFR-targeted therapy PMID:24686850
  • 31 candidate actionable alterations identified including ERBB, HDAC, PI3K family, JAK-STAT3, and MTOR-RPS6K signaling targets PMID:24686850

Sources

  • PMID:24686850 — Lin et al. (2014), WES/targeted sequencing of 139 ESCC cases identifying novel drivers and XPO1 as a therapeutic target.
  • PMID:24670651 — Chen et al. (2024), systematic review of oral microbiome in esophageal cancer (ESCC focus).

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