Distribution of somatic mutations of cancer-related genes according to microsatellite instability status in Korean gastric cancer

Abstract

In studies of the molecular basis of gastric cancer (GC), microsatellite instability (MSI) is one of the key factors. Somatic mutations found in GC are expected to contribute to MSI-high (H) tumorigenesis. We estimated somatic mutation distribution according to MSI status in 52 matched pair GC samples using the Ion Torrent Ion S5 XL with the AmpliSeq Cancer Hotspot panel.Seventy-five (9.8%) somatic variants consisting of 34 hotspot mutations and 41 other likely pathogenic variants were identified in 34 GC samples. The TP53 mutations was most common (35%, 26/75), followed by EGFR (8%, 6/75), HNF1A (8%, 6/75), PIK3CA (8%, 6/75), and ERBB2 (5%, 4/75). To determine MSI status, 52 matched pair samples were estimated using 15 MSI markers. Thirty-nine MS stable (S), 5 MSI-low (L), and 8 MSI-H were classified. GCs with MSI-H tended to have more variants significantly compared with GCs with MS stable (MSS) and MSI-L (standardized J-T statistic = 3.161 for number of variants; P = .002). The mean number of all variants and hotspot mutations per tumor samples only in GCs with MSI-H were 3.9 (range, 1–6) and 1.1 (range, 0–3), respectively. Whereas, the mean number of all variants and hotspot mutations per tumor samples only in GCs with MSS/MSI-L were 1 (0–5)/0.8 (0–1) and 0.5 (0–3)/0.8 (0–1), respectively.In conclusion, GC with MSI-H harbored more mutations in genes that act as a tumor suppressor or oncogene compared to GC with MSS/MSI-L. This finding suggests that the accumulation of MSIs contributes to the genetic diversity and complexities of GC. In addition, targeted NGS approach allows for detection of common and also rare clinically actionable mutations and profiles of comutations in multiple patients simultaneously. Because GC shows distinctive patterns related to ethnics, further studies pertaining to different racial/ethnic groups or cancer types may reinforce our investigations.

Dual prognostic role of 2‐oxoglutarate‐dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance

“…We also did not observe any prognostic significance of signature 1, which includes KDM6B , in either breast or renal clear cell cancer, which indirectly substantiates findings from two other reports on KDM6B not being a marker of good prognosis [40, 41]. Several other gene signatures have been reported for gastrointestinal cancers [42–46]. Interestingly, there is no overlap between our signature genes and those identified in these studies.…”

Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions

“…MSI is characterized by elevated mutation rates, including mutations of genes encoding targetable oncogenic signaling proteins [ 60 ]. MSI GCs have been shown to harbor more mutations in genes that act as tumor suppressors or oncogenes [ 61 ]. TCGA HotNet analysis of genes mutated within MSI tumors revealed common alterations in major histocompatibility complex class I genes, including beta - 2 microglobulin ( B2M ) and HLA - B [ 4 ].…”

Detection of gene mutations in gastric cancer tissues using a commercial sequencing panel

“…With regard to somatic mutations, it has been reported that TP53, KRAS, ARID1A, PIK3CA, ERBB3, PTEN and HLA-B are the commonly mutated genes in gastric cancer (4). In a previous study, TP53 mutations were reported to be the most common in gastric cancer samples, followed by mutations of EGFR, HNF1A, PIK3CA and ERBB2 (7). As of date, several drugs, with molecular targets, have been evaluated for their efficacy in treating cancers, which has been found to be associated with the genetic profile of patients.…”

“…Therefore, it is important to perform a comprehensive analysis of the relationships of gene alteration status and patient's characteristics. Park et al performed an NGS analysis using a targeted gene panel to detect common as well as rare mutations, and showed that the accumulation of microsatellite instability status contributes to the genetic diversity and complexities in gastric cancer (7).…”