Mutations Are Frequent in Esophageal Squamous Cell Carcinoma Associated with Chagasic Megaesophagus and Are Associated with a Worse Patient Outcome

Background: Chronic diseases such as chagasic megaesophagus (secondary to Chagas' disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.

Objective: We analyzed hotspot gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies. We also checked for correlations between the presence of mutations with patients' clinical and pathological features.

Methods: The study included three different groups of patients: i) 23 patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC); ii) 38 patients with esophageal squamous cell carcinoma not associated with chagasic megaesophagus (ESCC); and iii) 28 patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM). hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.

Results: mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases. In the CM/ESCC group, mutations were significantly associated with lower survival (mean 5 months), when compared to wild-type patients (mean 2.0 years). No other significant associations were observed between mutations and patients' clinical features or mutation profile.

Conclusion: This is the first report on the presence of mutations in esophageal cancer associated with chagasic megaesophagus. The detection of mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.