Gastric biomarkers: a global review

Abstract

Background: Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes.

Main body: This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability.

Conclusion: A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.

Keywords: Biomarkers; Gastric cancer; Therapy.

Fig. 1

Molecular subtypes of gastric cancer. a Gastric cancer cases are divided into subtypes: Epstein–Barr virus (EBV)-positive (red), microsatellite instability (MSI, blue), genomically stable (GS, green), and chromosomal instability (CIN, light purple) and ordered by mutation rate. Clinical (top) and molecular data (top and bottom) from 227 tumours profiled with all six platforms are depicted. b A flowchart outlines how tumours were classified into molecular subtypes. c Differences in clinical and histological characteristics among subtypes with subtypes coloured as in a, b. The plot of patient age at initial diagnosis shows the median, 25th and 75th percentile values (horizontal bar, bottom and top bounds of the box), and the highest and lowest values within 1.5 times the interquartile range (top and bottom whiskers, respectively). GE, gastroesophageal (reproduced with permission from The Cancer Genome Atlas Research Network (NATURE | VOL 513 | 11 SEPTEMBER 2014 [14])

Fig. 2

Key features of gastric cancer subtypes. This schematic lists some of the salient features associated with each of the four molecular subtypes of gastric cancer. Distribution of molecular subtypes in tumours obtained from distinct regions of the stomach is represented by inset charts (reproduced with permission from The Cancer Genome Atlas Research Network (NATURE | VOL 513 | 11 SEPTEMBER 2014 [14])

Fig. 3

Signalling pathway and targeted therapy in gastric cancer. Percentages signify the overall molecular characteristics in the disease: FGFR2 amplification (9 %), VEGF/VEGFR overexpression (36–40 %), EGFR amplification and overexpression (27–44 %), HER2 amplification and overexpression (7–34 %), c-MET amplification (10–15 %), kRAS mutation (2–20 %), Raf mutation (0–3 %), PI3K mutation (4–36 %), phospho-Akt expression (29–86 %), phospho-mTOR expression (60–88 %), PTCH1 overexpression (16%), SMO overexpression (12%), and HER3 mutations (10%, not shown). *No clinical trials of these agents have yet been reported in gastric cancer. ^‡No known numbers or percentages for these genes and pathways. Abbreviations: EGFR epidermal growth factor receptor, FGFR fibroblast growth factor receptor, GLI glioma-associated oncogene family zinc finger 1, HDAC histone deacetylase, HER human epidermal growth factor receptor, HGF hepatocyte growth factor, Hh Hedgehog, IGFR insulin-like growth factor receptor, MMP matrix metalloproteinase, mTOR mammalian target of rapamycin, PDGFR platelet-derived growth factor receptor, Ptch-1 protein patched homolog 1, Smo smoothened, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor (reproduced with permission from Wadhwa, R. et al. Nat. Rev. Clin. Oncol. 10, 643–655 (2013) [181])