Hypermutation and microsatellite instability in gastrointestinal cancers

// Kizuki Yuza 1 , Masayuki Nagahashi 1 , Satoshi Watanabe 2 , Kazuaki Takabe 3, 4 and Toshifumi Wakai 1 1 Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan 2 Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan 3 Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA 4 Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY 14203, USA Correspondence to: Masayuki Nagahashi, email: mnagahashi@med.niigata-u.ac.jp Keywords: hypermutation; microsatellite instability; immune checkpoint inhibitor; gastrointestinal cancer; precision medicine Received: September 15, 2017     Accepted: November 13, 2017     Published: December 01, 2017 ABSTRACT Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer. In gastrointestinal cancers, one of the leading causes of hypermutation is a defect in DNA mismatch repair, which results in microsatellite instability (MSI). This review will focus on the frequency, characteristics and genomic signature of hypermutated gastrointestinal cancers with MSI. Detection of tumor hypermutation in cancer is expected to not only predict the clinical benefit of immune checkpoint inhibitor treatment, but also to provide better surgical strategies for the patients with hypermutated tumors. Thus, in an era of precision medicine, identification of hypermutation and MSI will play an important role directing surgical and chemotherapeutic treatment.