Abstract 2721: Establishment of a catalog of somatic genetic alterations of Japanese cancer patients across multiple tumor types at Shizuoka Cancer Center
Authors: Kenmotsu Hirotsugu , Serizawa Masakuni , Nagashima Takeshi , Ohshima Keiichi , Hatakeyama Keiichi , Shimoda Yuji , Ohnami Shumpei , Maruyama Koji , Mochizuki Tohru , Akiyama Yasuto , Sugino Takashi , Urakami Kenichi , Kusuhara Masatoshi , Yamaguchi Ken 
Published: August 2019

Background: Recent progression of systematic tumor-molecular profiling study centered on genome sequencing have elucidated molecular signature underlying each tumor type. Tumor molecular profiling enables efficient identification of somatic genetic alterations as potential therapeutic targets. In January 2014, the Shizuoka Cancer Center of Japan launched Project HOPE, which is the first prospective molecular profiling study centered on genome sequencing across multiple tumor types in Japan. Herein, we describe the distributions of the tumor mutation burden (TMB; number of mutations/Mb), genetic alterations frequency, mutational signature across tumor types, and their associations with tissue of origin, histological type, carcinogenic factors, and ethnicity.

Methods: Between January 2014 and January 2017, 3,163 tumor samples from 3,011 patients who underwent surgery at the Shizuoka Cancer Center were collected with informed consent and subjected to whole-exome sequencing (WES) with an Ion Proton system. Corresponding peripheral blood samples were also subjected to WES for identification of tumor-specific genetic alterations. Oncogenic fusions were detected by targeted RNA sequencing. Among them, data of 2,126 primary tumor samples obtained from 2,091 patients without neoadjuvant chemotherapy and/or radiation therapy were selected for this study.

Results: The principal tumor types of ≥40 primary tumors were as follows (N, TMB): colon adenocarcinoma (COAD; 459, 3.6), rectal adenocarcinoma (READ; 366, 3.1), lung adenocarcinoma (LUAD; 290, 1.7), stomach adenocarcinoma (STAD; 221, 3.0), hepatocellular carcinoma (HCC; 112, 3.6), head and neck squamous cell carcinoma (HNSC; 112, 2.8), breast invasive ductal carcinoma (IDC; 82, 1.1), lung squamous cell carcinoma (LUSC; 81, 5.9). Approximately 8.9% of the samples (154 / 1,723) showed a high mutation burden above the threshold defined by the TMB distribution in each principal tumor type, and the mutation signature was related to a defect of DNA repair and exposure to environmental mutagens. In comparison of distribution of TMB in each tumor type between TCGA and this study, some differences in TMB distribution were observed, including LUAD, LUSC, and IDC. In gene mutations based on OncoKB site (October 2018), level 1 or 2 of somatic gene mutation was frequently observed in glioma (84.6%), gastrointestinal stromal tumor (77.4%), melanoma (40.0%), and LUAD (40.0%).

Conclusions: This established catalog of somatic genetic alterations across multiple tumor types in Japanese cancer patients can contribute as benchmark to clinical-trial design with the aim of expanding the number of patients suitable for molecular-targeted therapies in Japan. Based on these data, we are planning clinical trials of molecular-targeted therapies for patients with solid tumor harboring gene alterations.

Citation Format: Hirotsugu Kenmotsu, Masakuni Serizawa, Takeshi Nagashima, Keiichi Ohshima, Keiichi Hatakeyama, Yuji Shimoda, Shumpei Ohnami, Koji Maruyama, Tohru Mochizuki, Yasuto Akiyama, Takashi Sugino, Kenichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi. Establishment of a catalog of somatic genetic alterations of Japanese cancer patients across multiple tumor types at Shizuoka Cancer Center [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2721.