Chapter 17 - Gastric Cancers: A Molecular Roadmap for Patient Stratification and Targeted Therapies

Abstract

Gastroesophageal adenocarcinoma (GEA) has long been one of the most common cancer worldwide, yet its underlying molecular abnormalities were only recently described. Advances in genomics, epigenetics, transcriptomics and proteomics, amongst others, allowed an unprecedented insight into the molecular mechanisms driving gastric and esophageal cancer carcinogenesis. Spearheaded by the Cancer Genome Atlas project, molecular classification of GEA revealed different subtypes, based on microsatellite instability, Epstein-Barr virus positivity, somatic copy-number variation and chromosomal instability, whilst other groups provided classifications based different characteristics, namely specific gene expression signatures, impaired DNA repairs pathways and mutational load. Microsatellite instability remains one of the most important biomarkers in GEA, as it is associated with a better prognosis and significant responses to immuno-oncology agents. Current therapeutics strategies for GEA include targeting receptor tyrosine kinase amplifications (HER-2, EGFR or c-MET), DNA repair pathways (BRCA1/2 mutations, ATM-loss), angiogenesis (VEGR, VEGFR2) or immune checkpoint inhibition (PD-1/-L1 axis, CTLA-4). Novel targets in GEA were described, with promising clinical results, and involve the tumoural microenvironment (matrix metalloproteinase), tight gap junction (Claudin 18.2) and the WNT developmental pathway (DKK-1). Potential futures approaches include targeting epigenetics modification, for example micro-RNAs, DNA methylation and histone acetylation. In conclusion, recent advances in oncogenomics enabled the identification of a multitude of therapeutic targets. As such, solid biomarker work that integrate all the available data is needed to guide treatment selection; that is undoubtably what will be of most benefit for GEA patients