Early TP53 Alterations Shape Gastric and Esophageal Cancer Development

Simple Summary Recent evidence establishes that gastric and esophageal (GE) adenocarcinomas are similar cancers at cellular, genomic, and epigenomic levels. Human GE adenocarcinomas develop TP53 mutations at early stages of malignant progression. This contrasts with other gastrointestinal adenocarcinomas, including sporadic colorectal and pancreatic adenocarcinomas, where TP53 alterations occur late. Exposure of the esophagus and stomach to environmental risk factors contributes to the selection of early TP53 mutations and subsequent chromosomal instability, which then lead to activation of mitogen and cell cycle pathways in GE adenocarcinomas by way of focal amplifications rather than mutations. While early TP53 mutations enable GE adenocarcinoma development, they also expose therapeutic vulnerabilities that should be prime for targeted therapy directed against the DNA damage response. Abstract Gastric and esophageal (GE) adenocarcinomas are the third and sixth most common causes of cancer-related mortality worldwide, accounting for greater than 1.25 million annual deaths. Despite the advancements in the multi-disciplinary treatment approaches, the prognosis for patients with GE adenocarcinomas remains poor, with a 5-year survival of 32% and 19%, respectively, mainly due to the late-stage diagnosis and aggressive nature of these cancers. Premalignant lesions characterized by atypical glandular proliferation, with neoplastic cells confined to the basement membrane, often precede malignant disease. We now appreciate that premalignant lesions also carry cancer-associated mutations, enabling disease progression in the right environmental context. A better understanding of the premalignant-to-malignant transition can help us diagnose, prevent, and treat GE adenocarcinoma. Here, we discuss the evidence suggesting that alterations in TP53 occur early in GE adenocarcinoma evolution, are selected for under environmental stressors, are responsible for shaping the genomic mechanisms for pathway dysregulation in cancer progression, and lead to potential vulnerabilities that can be exploited by a specific class of targeted therapy.