Detection of a novel panel of 24 genes with high frequencies of mutation in gastric cancer based on next-generation sequencing

Background: Gastric cancer is a leading cause of cancer-related mortality worldwide. Many somatic mutations have been identified based on next-generation sequencing; they likely play a vital role in cancer treatment selection. However, next-generation sequencing has not been widely used to diagnose and treat gastric cancer in the clinic.

Aim: To test the mutant gene frequency as a guide for molecular diagnosis and personalized therapy in gastric cancer by use of next-generation sequencing.

Methods: We constructed a panel of 24 mutant genes to detect somatic nucleotide variations and copy number variations based on a next-generation sequencing technique. Our custom panel included high-mutation frequency cancer driver and tumour suppressor genes. Mutated genes were also analyzed using the cBioPortal database. The clinical annotation of important variant mutation sites was evaluated in the ClinVar database. We searched for candidate drugs for targeted therapy and immunotherapy from the OncoKB database.

Results: In our study, the top 16 frequently mutated genes were TP53(58%), ERBB2(28%), BRCA2 (23%), NF1 (19%), PIK3CA (14%), ATR (14%), MSH2 (12%), FBXW7 (12%), BMPR1A (12%), ERBB3 (11%), ATM (9%), FGFR2 (8%), MET (8%), PTEN (6%), CHD4 (6%), and KRAS (5%). TP53 is a commonly mutated gene in gastric cancer and has a similar frequency to that in the cBioPortal database. 33 gastric cancer patients (51.6%) with microsatellite stability and eight patients (12.5%) with microsatellite instability-high were investigated. Enrichment analyses demonstrated that high-frequency mutated genes had transmembrane receptor protein kinase activity. We discovered that BRCA2, PIK3CA, and FGFR2 gene mutations represent promising biomarkers in gastric cancer.

Conclusion: We developed a powerful panel of 24 genes with high frequencies of mutation that could detect common somatic mutations. The observed mutations provide potential targets for the clinical treatment of gastric cancer.