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

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.

Tumor mutation burden as a biomarker for lung cancer patients treated with pemetrexed and cisplatin (the JIPANG‐TR)

“…Although the reason for the discrepancy remains unclear, it might be dependent on the mode of action of the regimen. Several factors influence high TMB status 12,13 . Genomic‐unstable tumors tend to harbor higher TMB.…”

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

“…In addition, peripheral blood was collected as a pair control for excluding germline mutation. Details of experimental protocols have been described previously 5,7,20‐23 …”

“…The expression signature/score was calculated from the average of genes in unique gene sets corresponding to each individual signature (TP53 inactivation, 8 CIN, 9‐11 methylation, 12 PI3K/mTOR CMAP UP, 13‐15 and T cell‐inflamed GEP 17‐19 ). To suppress influence of gene expression derived from normal tissue, the signature analysis was performed using T/N expression ratio 5 …”

“…Although TMB analyses across the globe are performed using WES, most cancers are determined to be TMB low (TMB ≤ 5 mutation/Mb) 1,5 . Driver mutations in exon regions were occasionally found to be absent in diverse tumor types, 6,7 implying the presence of somatic alterations that were undetectable only by WES.…”

Mutational concordance analysis provides supportive information for double cancer diagnosis

“…Peripheral blood was also collected as a paired control to exclude germline mutations. The details of the experimental protocols used have been described previously [ 4 – 9 ]. Briefly, tumor and normal tissues were immediately frozen in liquid nitrogen prior to DNA extraction.…”