Early TP53 Alterations Shape Gastric and Esophageal Cancer Development.

Pranshu Sahgal,James M Cleary,Rona Yaeger,Walid K Chatila,Deepa T Patil,Brandon M Huffman,Nilay S Sethi

doi:10.3390/cancers13235915

Abstract

Simple SummaryRecent 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.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.

Highlights

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A separate study demonstrated that 46% of BE lesions that progress to high grade dysplasia or esophageal adenocarcinoma harbor TP53 mutations, Cancers 2021, 13, 5915 genome sequencing of 23 paired human BE and esophageal adenocarcinoma samples showed that the degree of aneuploidy increases in the progression to cancer, suggesting that early inactivation of TP53 might be a critical step in allowing the development of aneuploidy [20]
Why are early TP53 mutations selected for in upper, relative to lower, GI adenocarcinomas? Is it because gastric and esophageal cells are more susceptible to TP53 mutations than colorectal cells, implicating the cell of origin as the culprit? Or rather, is it the environmental context of the upper, compared to the lower, GI tract that selects for TP53 mutations? An examination of sporadic versus colitis-associated cancer (CAC) argues that there is a substantial contribution from environmental context

Summary

Gastric and Esophageal Adenocarcinomas Are Similar Cancers

Molecular, genetic, and epigenomic analyses of adenocarcinomas of the stomach and esophagus demonstrate that these cancers are highly related. Gastric and esophageal adenocarcinomas appear to arise from a shared tissue of origin. A mouse model of Barrett’s esophagus (BE), widely considered the precursor lesion to esophageal adenocarcinoma, showed that Lgr5+ gastric cardia stem cells are potentially the cells of origin [1]. Esophageal adenocarcinomas display chromatin profiles that mirror those found in gastric tissue (H3K9me, H3K4me, H3K4me, H3K9ac, H3K36me). Beyond the common ancestry of these cancers, deeper evaluation of human gastric and esophageal adenocarcinomas demonstrates shared molecular features. By appreciating the cellular and molecular resemblance between gastric and esophageal adenocarcinomas, can we generate better models for the premalignant and malignant states, but we can think about treating patients with these cancers in similar ways

TP53 Alteration Is an Early Event in GE Premalignancy

Context Matters

Therapeutic Vulnerabilities Imparted by Early TP53 Mutations

Findings

Conclusions