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

Tumor mutational burden analysis using whole exome sequencing highlights features of a tumor with a number of mutations or known driver alterations. However, 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 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 mutation/Mb). This tendency was observed in The Cancer Genome Atlas data set as well. Furthermore, 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, T cell inflamed gene expression profiling signature is a potential marker for prediction of immune checkpoint inhibitor response, and part of ultralow tumor mutational burden tumor populations highly express this signature. 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.