Novel biomarkers for the identification and targeted therapy of gastric cancer

Abstract

Gastric cancer development follows the pathologic pattern such that chronic inflammation in the gastric mucosa progressively transforms normal mucosa into atrophy, intestinal metaplasia, adenoma/dysplasia and eventually invasive and metastatic tumors. The accumulation of multiple genetic and epigenetic alterations leads to the dysregulation of oncogenes and tumor suppressors, which was considered as the driver behind events during the tumorigenesis. Almost all gastric cancers are adenocarcinomas, which share considerable heterogeneity with distinct morphology, pathogenesis and clinical behavior. Therefore, identifying subtypes of gastric cancers with molecular and genetic features will be beneficial for the early identification and selection of new effective agents for targeted treatment. High-throughput sequencing techniques such as whole genomic, epigenome and transcriptome sequencing and proteomics platforms have identified major genomic characteristics that exhibit identification and prognostic impacts and distinct response patterns. In this article, the authors aim to summarize the information regarding the most promising molecules that may have clinical application as non-invasive biomarkers and therapy targets.

Keywords:

• biomarker
• gastric cancer
• lncRNA
• miRNA
• promoter methylation
• targeted therapy

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Molecular classification according to gene expression patterns and genomic basis, classified gastric cancer into subtypes with different genetic features and chemotherapeutic sensitivity.

• Epigenetic alterations, including aberrant DNA methylation, is a hallmark of gastric cancer. Non-coding RNA, like miRNAs and lncRNAs play important regulatory roles in gastric mucosa carcinogenesis.

• hMLH1, APC, TIMP3 and E-cadherin in combination, RNF180, Reprimo, SLC19A3, RUNX3, CYP26B1, KCNA4 and secreted frizzled-related protein 2 methylation in serum/plasma are non-invasive biomarkers in gastric cancer.

• miRNAs like miR-106a/let-7a, miR-17/miR-106a, miR-378, miR-451, miR-486 and combination of miR-1, -20a, -27a, -34 and 423-5p in circulation are potential non-invasive biomarkers for identifying gastric cancer.

• lncRNAs like CUDR, LSINCT-5 and PTENP1 in serum might represent new complementary non-invasive markers for early identification of gastric cancer.

• Based on gene expression patterns, gastric cancer was divided into subtypes: proliferative, metabolic and mesenchymal. Metabolic subtype benefits with 5-fluorouracil treatment. Mesenchymal subtypes are particularly sensitive to PI3K-AKT-mTOR inhibitors.

• Targeted agents, trastuzumab is a monoclonal antibody targeting HER2, everolimus is a novel macrolide derivative of rapamycin. High baseline plasma levels of VEGF-A, tumor neuropilin-1 gastric patients were more sensitive to bevacizumab treatment.

• Various studies have delineated the gastric cancer subtypes on the basis of molecular signature together with distinct clinical phenotypes, thereby laying us the groundwork for the development of personalized medicine as well improved clinical management of cancer.

Notes