Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy

• Published in: Cancer science 2019-08, Vol.110 (8), p.2620-2628
• Main 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
• Format: Article
• Language: English
• Subjects: Apoptosis; Cancer therapies; Carcinogenesis - genetics; Carcinogenesis - pathology; Deoxyribonucleic acid; DNA; DNA Mismatch Repair - genetics; DNA Repair - genetics; Gene expression; Genome, Human - genetics; Genomes; Genomics; Hepatocellular carcinoma; High-Throughput Nucleotide Sequencing - methods; Humans; Hypopharynx; immune checkpoint blockade; Immune checkpoint inhibitors; Immunotherapy; Japan; Microsatellite Instability; Mismatch repair; Monoclonal antibodies; Mutation; Mutation - genetics; mutational signature; Neoplasms - genetics; Neoplasms - pathology; Original; Pembrolizumab; Smoking; Software; Solid tumors; Targeted cancer therapy; Tumor Burden - genetics; Tumor microenvironment; Tumor Microenvironment - genetics; tumor mutational burden; Tumorigenesis; Tumors; Ultraviolet radiation; Whole Exome Sequencing - methods
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14087

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. 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.