Characterization of tumors with ultralow tumor mutational burden in Japanese cancer patients

• Published in: Cancer science 2020-10, Vol.111 (10), p.3893-3901
• Main Authors: Hatakeyama, Keiichi, Nagashima, Takeshi, Ohshima, Keiichi, Ohnami, Sumiko, Ohnami, Shumpei, Shimoda, Yuji, Naruoka, Akane, Maruyama, Koji, Iizuka, Akira, Ashizawa, Tadashi, Mochizuki, Tohru, Urakami, Kenichi, Akiyama, Yasuto, Yamaguchi, Ken
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Aged; Biomarkers, Tumor - genetics; Cancer; Cell cycle; Copy number; Datasets; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; gene expression signature; Genetics, Genomics, and Proteomics; Genomes; Genomic instability; Genomics; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - adverse effects; Immune Checkpoint Inhibitors - therapeutic use; Inflammation; Japan; Japanese Cancer Genome Atlas; Lymphocytes T; Male; Medical research; Middle Aged; Mutation; Mutation - genetics; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Original; p53 Protein; Phosphatidylinositol 3-Kinases - genetics; Solid tumors; TMB ultralow; TOR protein; TOR Serine-Threonine Kinases - genetics; TP53 inactivation; tumor mutational burden; Tumor Suppressor Protein p53 - genetics; Tumorigenesis; Tumors; Whole Exome Sequencing
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14572

Tumor mutational burden analysis using whole‐exome sequencing highlights features of tumors with various mutations or known driver alterations. Cancers with few changes in the exon regions have unclear characteristics, even though low‐mutated tumors are often detected in pan‐cancer analysis. In the present study, we analyzed tumors with low tumor mutational burden listed in the Japanese version of The Cancer Genome Atlas, a data set of 5020 primary solid tumors. Our analysis revealed that detection rates of known driver mutations and copy number variation were decreased in samples with tumor mutational burden below 1.0 (ultralow tumor), compared with those in samples with low tumor mutational burden (≤5 mutations/Mb). This trend was also observed in The Cancer Genome Atlas data set. In the ultralow tumor mutational burden tumors, expression analysis showed decreased TP53 inactivation and chromosomal instability. TP53 inactivation frequently correlated with PI3K/mTOR‐related gene expression, implying suppression of the PI3K/mTOR pathway in ultralow tumor mutational burden tumors. In common with mutational burden, the T cell‐inflamed gene expression profiling signature was a potential marker for prediction of an immune checkpoint inhibitor response, and some ultralow tumor mutational burden tumor populations highly expressed this signature. Our analysis focused on how these tumors could provide insight into tumors with low somatic alteration that are difficult to detect solely using whole‐exome sequencing. This study describes our analysis of tumors with a low tumor burden level in the Japanese version of The Cancer Genome Atlas (JCGA), a data set of 5020 primary solid tumors. In the ultralow tumor mutational burden tumors, expression analysis showed decreased TP53 inactivation and chromosomal instability. Our analysis focuses on how these tumors can provide insight into tumors with low somatic alteration that are difficult to detect solely by whole exome sequencing.