Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy. Issue 8 (24th June 2019)

• Record Type: Journal Article
• Authors: Hatakeyama, Keiichi; Nagashima, Takeshi; Ohshima, Keiichi; Ohnami, Sumiko; Ohnami, Shumpei; Shimoda, Yuji; Serizawa, Masakuni; Maruyama, Koji; Naruoka, Akane; Akiyama, Yasuto; Urakami, Kenichi; Kusuhara, Masatoshi; Mochizuki, Tohru; Yamaguchi, Ken
• Is Part Of: Cancer science. Volume 110:Issue 8(2019)
• Page Start: 2620
• Page End: 2628
• Publication Date: 2019-06-24
• Subjects: gene expression -- immune checkpoint blockade -- mutational signature -- tumor microenvironment -- tumor mutational burden; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14087
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Tumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole‐exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures—microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double‐strand break repair, and Signature 16—were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune‐related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation‐driven tumorigenesis. Abstract : By applying whole‐exome sequencing and microarray technologies for high‐throughput genomic and transcriptional analysis, this study investigates the mutational burden and signatures in a large cohort of tumor samples of different histology from Japanese patients. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune‐related genes, reflecting differences in the immune context of the tumor microenvironment.