Molecular profiling and metabolic dysregulation in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a malignancy with rising incidence rates and poor prognosis in Western countries, with a 5-year survival rate of approximately 35% to 45%. The molecular mechanisms underlying EAC carcinogenesis remain only partially understood. Extensive genomic analyses have identified frequent somatic structural rearrangements, copy number alterations, and single nucleotide mutations, revealing a high mutation burden. The heterogeneity of EAC continues to pose unresolved challenges regarding its classification, prevention, early diagnostic programs, and treatment strategies, ultimately hindering the development of targeted therapies for more personalized treatment approaches. We analyzed the genetic profiles of EAC samples from 164 naïve patients who had not received chemo-radiotherapy. Through high-coverage next-generation sequencing technology and a customized gene panel, we confirmed that TP53 is the most frequently mutated gene, with a mutation rate of 67.1%, further revealing a complex mutational spectrum in EAC, consisting mainly of point mutations but also insertions and deletions. Missense mutations in TP53 were associated with poorer cancer-specific survival (Log Rank P = 0.0197). We identified disruptive mutations in the HNF1α gene in 7 cases, which had not previously been associated with this tumor type, and all accompanied by alterations in other genes. Future studies will be needed to further investigate the role of HNF1α as a tumor suppressor gene to fully elucidate its functions in tumor development and progression. The metabolic profiling of esophageal carcinoma cell lines (OE19 and FLO-1) revealed distinct metabolic dependencies. The FLO-1 cell line exhibits a higher metastatic potential and a predominantly glycolytic metabolism, while OE19 preferentially rely on oxidative phosphorylation and exhibit marked oxidative stress. This difference is reflected in the mitochondrial network, which appears more fragmented and depolarized in OE19 cells compared to FLO-1. These findings suggest a correlation between mitochondrial dynamics and cellular metabolism that may play a role in tumor aggressiveness.