K. Yuza1, H. Ichikawa1, T. Hanyu1, T. Ishikawa1, Y. Shimada1, J. Sakata1, H. Kameyama1, T. Kobayashi1, H. Izutsu2, K. Kodama2, K. Takabe3, T. Wakai1, M. Nagahashi1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata City, NIIGATA, Japan 2Life Innovation Research Institute, Denka Innovation Center, Denka Co., Ltd.,Diagnostics Research Department,Machida City, TOKYO, Japan 3Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NEWYORK, USA
Introduction: There has been increasing evidence indicating importance of microsatellite instability (MSI) and mutations in the DNA mismatch repair pathway in association with the efficacy of 5-FU and immune checkpoint inhibitors in patients with gastrointestinal cancers. MSI has been shown to correlate with high somatic mutational rates in cancer as determined by whole exome sequencing. Some gene mutations, such as BRAF mutations, are known to be associated with MSI-high status (MSI-H). The activin type II receptors (ACVR2), which modulate signals for the transforming growth factor beta superfamily of ligands, are frequently mutated in MSI-H colorectal cancer. However, the incidence of ACVR2 mutations in gastric cancer patients has not well investigated yet. The aim of this study is to reveal the incidence of MSI-H and ACVR2A mutations, and to examine the association between the MSI-H and ACVR2A mutations in gastric cancer patients.
Methods: DNA samples extracted from 124 archived FFPE tumor tissues of Japanese patients with gastric cancer (stage I-IV), who were operated at Niigata University Medical and Dental Hospital or Niigata Cancer Center Hospital, were analyzed with the next generation sequencing-based comprehensive genomic test platform (CancerPlex). Overall mutational burden, mutations in DNA mismatch repair genes and MSI status (MSI-H or microsatellite stable; MSS) were evaluated.
Results: All 124 gastric cancer patients were successfully analyzed by comprehensive genomic test platform. 13 out of 124 patients (10.4%) showed MSI-H status and 111 patients showed MSS status. The median of mutation burden in patients with MSI-H is 35 (range: 19-102), while that in patients with MSS is 14 (range: 4-42) (P < 0.001). Mutations in mismatch repair genes were found in 6 of 13 (46.2.8%) MSI-H patients (1 in MLH1, 2 in MSH6, 2 in PMS2, and 1 in both MSH6 and PMS2). Interestingly, 10 of 13 MSI-H patients (76.9%), which is 8.0% of all gastric cancer examined, showed ACVR2A mutation, and no patients with MSS status (0%) showed ACVR2A mutation (P < 0.001).
Conclusion: 13 (10.4%) gastric cancer patients showed MSI-H status, and all of 10 that showed ACVR2A mutation has MSI-H. Our results implicate an intriguing possibility that ACVR2A mutations may be an affordable surrogate to identify MSI-H.