Abstract 3422: Genomic landscape of Japanese cancer patients across multiple tumor types: Prospective molecular profiling study of 3,022 patients at Shizuoka Cancer Center

Abstract

Abstract Background: Cancer genome sequencing enables efficient identification of genetic alterations as potential therapeutic targets, representing a fundamental component of precision oncology to make therapeutic decisions based on individualized genetic signatures. 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. 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, and carcinogenic factors. Methods: Between January 2014 and April 2017, 3,174 tumor samples from 3,022 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. Samples with estimated tumor purity < 20% were excluded because of the risk of false negatives, leaving 2,899 samples (91%) in the final analysis. Results: Overall, 2,642 samples were derived from the primary tumor, with a median TMB of approximately 2.7. The principal tumor types of ≥40 primary tumors were as follows (N, TMB): colorectal adenocarcinoma (CRAD; 905, 3.3), lung adenocarcinoma (LUAD; 324, 1.6), gastric adenocarcinoma (GAD; 272, 3.0), head and neck squamous cell carcinoma (HNSC; 164, 2.6), breast invasive ductal carcinoma (BIDC; 138, 1.1), hepatocellular carcinoma (HCC; 124, 3.6), lung squamous cell carcinoma (LUSC; 79, 5.6), and gastrointestinal stromal tumor (GIST; 41, 0.7). Approximately 7.8% of the samples (160/2,047) 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. Dominant oncogenic pathways based on the profile of genetic alterations in each tumor type were as follows: Wnt (CRAD), receptor tyrosine kinase (LUAD, GIST), TP53 (GAD, HNSC, LUSC), PI3K (BIDC), and chromatin modification (HCC). GIST was the tumor type with the highest proportion of clinically actionable genetic alterations, followed by BIDC and LUAD. Conclusions: This is the first report of a prospective genome sequencing analysis across multiple tumor types in Japan. The resulting mutational profile can provide a landscape of commonalities and differences in genetic profiles among tumor types in Japanese patients with cancer, and can contribute to planning a basket study for expanding the patients suitable for treatment with molecular-targeted drugs. Citation Format: Masakuni Serizawa, Takeshi Nagashima, Keiichi Ohshima, Keiichi Hatakeyama, Yuji Shimoda, Shumpei Ohnami, Kouji Maruyama, Takashi Sugino, Tohru Mochizuki, Yasuto Akiyama, Kenichi Urakami, Masatoshi Kusuhara, Medical staff and experimental staff of the Shizuoka Cancer Center, Ken Yamaguchi. Genomic landscape of Japanese cancer patients across multiple tumor types: Prospective molecular profiling study of 3,022 patients at Shizuoka Cancer Center [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3422.