Exploring the origins of esophagogastric junction cancer through omics: A focus on the Siewert II subclassification

Esophagogastric junction adenocarcinoma (EGJAC) is a distinct and increasingly prevalent malignancy associated with a poor survival. Among EGJACs, Siewert type II tumors pose particular challenges because of their heterogeneous origins, molecular diversity, and the absence of consensus regarding classification and management. Although anatomical classifications remain clinically useful, they inadequately reflect the biological complexity of these tumors. Recent molecular and omics advances have clarified esophagogastric junction tumorigenesis by revealing the interactions between reflux-related conditions and intrinsic and environmental risk factors. Accumulating evidence suggests that Siewert II tumors may originate from multiple cellular populations within the junctional zone, including Barrett's metaplasia, cardiac-type epithelium, and gastric mucosa, each associated with distinct pathogenetic pathways. Genomic and transcriptomic studies have identified key oncogenic drivers and pathways, supporting biologically driven subclassification and potentially explaining variability in the therapeutic response. Currently, surgical and systemic treatment strategies for Siewert II tumors are largely extrapolated from esophageal and gastric cancer paradigms. Integrating molecular profiling with anatomical classification may improve clinical trial stratification and enable more personalized therapeutic approaches. This review summarizes the current evidence on the epidemiology, risk factors, histopathology, and molecular landscape of Siewert II adenocarcinomas, emphasizing the need for integrative classification frameworks to advance precision oncology and improve the patient outcomes.