Is esophageal cancer solely determined by genetics?

Is Esophageal Cancer Genetic?

Esophageal cancer is not solely determined by genetics, but rather results from a complex interplay between genetic factors, environmental exposures, and lifestyle factors, with heredity playing a modest role in most cases except for rare familial syndromes. 1

Genetic Factors in Esophageal Cancer

Inherited Genetic Risk

• The role of inherited genetic variants on esophageal squamous cell carcinoma (OSCC) risk is modest apart from rare familial cases 1
• Tylosis, an autosomal dominant disorder caused by germline mutation in RHBDF2 (encoding for iRhom2), is associated with a 90% cumulative risk of OSCC by age 70 1
• Host genetics contribute up to one-third of the risk for sporadic Barrett's esophagus (BE) and esophageal adenocarcinoma (OAC) development, with approximately 7% of cases being familial 1

Genetic Susceptibility Loci

• Large-scale genome-wide association studies (GWAS) in China have identified susceptibility loci for OSCC at:
  • 10q23 (encoding PLCE1; associated with growth, differentiation and apoptosis)
  • 5q31.2 (encoding TMEM173; associated with Type 1 interferon response)
  • 17p13.1 (encoding ATP1B2; near TP53)
  • HLA class II region (6p21.32) in high-risk areas 1
• For OAC, GWAS studies have identified risk loci linked to:
  • Esophageal embryonic development (FOXF1, BARX1)
  • Host immune response (MHC locus 16.24)
  • Cellular proliferation and transformation (CRTC1) 1

Environmental and Lifestyle Risk Factors

For Esophageal Squamous Cell Carcinoma (OSCC)

• Recurrent chemical or physical insult to the esophageal mucosa increases OSCC risk 1
• In non-endemic areas, OSCC is predominantly associated with tobacco and alcohol use 1, 2
• Low intake of fruits and vegetables is another established risk factor 2
• Thermal injury from hot beverages in certain regions contributes to risk 2

For Esophageal Adenocarcinoma (OAC)

• Gastro-esophageal reflux is the most important risk factor for OAC (OR 4.64,95% CI 3.28-6.57) 1
• Obesity, particularly central (visceral) obesity, is the second strongest risk factor 1
• Smoking is a moderately strong risk factor for OAC 1
• Male gender carries higher risk (male:female incidence 7:1) 1
• High red meat intake and lower fruit/vegetable intake increase risk 1
• Helicobacter pylori infection demonstrates an inverse association with BE/OAC risk 1

Molecular Pathogenesis

Somatic Genetic Alterations in OSCC

• Dysregulation of TP53 and cell cycle regulators are prominent characteristics of OSCC 1
• Most commonly mutated genes include TP53 (91%), MLL2 (17%), and NFE2L2 (14%) 1
• Amplifications frequently identified in SOX2/TP63 (48%) and FGFR1 (12%) 1
• CDKN2A was inactivated in 76% of tumors and amplification of CCND1 was present in 57% 1

Somatic Genetic Alterations in OAC

• OAC has a high mutation burden compared to other cancers 1
• Structural alterations dominate the OAC landscape, with common copy number alterations 1
• Amplifications frequently found in receptor tyrosine kinases (ERBB2, EGFR, KRAS, FGFR2), cell cycle regulators (CCND1, CDK6), and transcription factors (MYC, GATA4, GATA6) 1
• Dysregulation of p53 signaling plays a key role in progression of Barrett's esophagus to invasive OAC 1

Clinical Implications

Genetic Testing and Screening

• The American College of Physicians and other medical organizations do not recommend routine genetic testing for esophageal cancer except in cases with strong family history 2
• For most patients, screening should focus on those with established risk factors rather than genetic predisposition 2

Prevention Strategies

• Primary focus for esophageal cancer prevention should remain on established risk factors, particularly tobacco and alcohol cessation 2
• Unlike oropharyngeal cancers, HPV-targeted prevention strategies are not supported for esophageal cancer 2
• The molecular profile of OSCC is consistent with HPV-negative squamous cell carcinoma 1, 2

Risk Modification

• Genetic variability in detoxification processes may modify environmental influences on OSCC susceptibility 1
• The genetically determined host response to inflammation caused by germline variation in inflammation response genes may determine individual BE and OAC risk 1

In summary, while genetic factors contribute to esophageal cancer risk, the disease is primarily driven by a combination of environmental exposures, lifestyle factors, and acquired somatic mutations, with hereditary factors playing a more significant role only in rare familial cases.