What is the pathogenesis of esophageal cancer?

Pathogenesis of Esophageal Cancer

Esophageal cancer develops through distinct pathogenic pathways for the two major subtypes—squamous cell carcinoma (OSCC) and adenocarcinoma (OAC)—involving progressive genetic and epigenetic alterations that lead to dysregulation of cell cycle control, DNA repair mechanisms, and cellular signaling pathways.

Pathogenesis of Esophageal Squamous Cell Carcinoma (OSCC)

Histological Progression

• OSCC develops through a sequence from basal cell hyperplasia to low-grade dysplasia, high-grade dysplasia, carcinoma in situ, and finally invasive carcinoma 1
• These precancerous lesions can be identified endoscopically as Lugol's voiding patches and biopsied for diagnosis 1

Molecular Alterations

• TP53 mutations are the most common genetic alteration in OSCC (91% of cases), leading to loss of genomic integrity and cell cycle dysregulation 1
• Other frequently mutated genes include MLL2 (17%) and NFE2L2 (14%), contributing to chromatin remodeling dysfunction and altered cellular stress responses 1
• Amplifications commonly occur in SOX2/TP63 (48%) and FGFR1 (12%), affecting cellular differentiation and growth signaling 1
• Cell cycle dysregulation is prominent with CDKN2A inactivation in 76% of tumors and CCND1 amplification in 57% 1

Environmental Triggers

• Recurrent thermal injury from hot beverages contributes to regional variations in OSCC incidence, particularly in areas like Northern Iran 1
• Chronic exposure to carcinogens (tobacco, alcohol) causes DNA damage with a characteristic mutational profile 1
• Despite previous suggestions, HPV infection appears to have limited causative effect in OSCC based on molecular profiling from The Cancer Genome Atlas (TCGA) 1

Pathogenesis of Esophageal Adenocarcinoma (OAC)

Barrett's Esophagus Progression

• OAC arises primarily from Barrett's esophagus, a metaplastic condition where normal squamous epithelium is replaced by columnar intestinal-type mucosa 1
• Chronic gastroesophageal reflux (acid and bile) causes DNA damage through reactive oxygen species and nitric oxide production, leading to a characteristic A>C transversion mutational profile 1
• Progression from Barrett's esophagus to OAC occurs in 0.12-0.6% of patients annually through accumulation of genetic alterations 1

Key Molecular Events

• Two primary mechanisms drive progression to OAC:
  1. Stepwise acquisition of tumor suppressor gene losses (CDKN2A, TP53, SMAD4) and chromatin modifier mutations 1
  2. Genome doubling events in TP53-mutant cells leading to large-scale chromosomal instability and aneuploidy 1
• OAC has a high mutation burden (9.9/Mb) compared to other cancers, with structural alterations dominating the genomic landscape 1
• Amplifications frequently occur in receptor tyrosine kinases (ERBB2, EGFR, KRAS, FGFR2), cell cycle regulators (CCND1, CDK6), and transcription factors (MYC, GATA4, GATA6) 1

Clonal Evolution

• Greater clonal diversity in Barrett's esophagus is associated with increased risk of progression to OAC 1
• Epigenetic modifications, particularly DNA methylation, are common in both Barrett's esophagus and OAC 1, 2
• Promoter hypermethylation of CDKN2A (p16INK4a) is frequent and associated with neoplastic progression 1

Genetic Susceptibility Factors

OSCC Susceptibility

• Tylosis, an autosomal dominant disorder caused by RHBDF2 germline mutation, confers a 90% cumulative risk of OSCC by age 70 1
• GWAS studies have identified susceptibility loci at 10q23 (PLCE1), 5q31.2 (TMEM173), 17p13.1 (ATP1B2), and HLA class II region (6p21.32) 1

OAC Susceptibility

• Host genetics contribute up to one-third of the risk for sporadic Barrett's esophagus and OAC development 1
• GWAS studies have identified risk loci related to esophageal embryonic development (FOXF1, BARX1), host immune response (MHC locus), and cellular proliferation (CRTC1) 1
• Approximately 7% of Barrett's esophagus and OAC cases may be familial 1

Molecular Subtypes with Therapeutic Relevance

• Three molecular subgroups of OAC have been identified through whole genome sequencing:
  1. Defective homologous recombination repair (potential sensitivity to PARP/ATR inhibitors or platinum chemotherapy)
  2. T>G mutation pattern with high mutational load (potential response to immunotherapy)
  3. C>A/T mutation pattern associated with aging 1
• Dysregulated pathways with therapeutic potential include cell cycle regulators, tyrosine kinase receptors, and chromatin remodeling pathways 1
• Co-amplification of receptor tyrosine kinases (e.g., ERBB2 and EGFR) is common in OAC and may contribute to treatment resistance 1

Understanding these pathogenic mechanisms is critical for developing targeted therapies and improving outcomes for patients with esophageal cancer.