Open AccessMutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy
Author(s) -
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
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14087
Subject(s) - microsatellite instability , dna mismatch repair , carcinogenesis , biology , cancer research , exome sequencing , mutation , context (archaeology) , immune checkpoint , transcriptome , immune system , cancer , exome , genome instability , genetics , immunotherapy , microsatellite , gene , dna damage , colorectal cancer , gene expression , allele , dna , paleontology
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.