Estimating tumor mutational burden across multiple cancer types using whole-exome sequencing

作者：Chuang Zhou, Chen Song, Fei Xu, Jinwang Wei, Xiaoyu Zhou, Zhiqiang Wu, Longshuan Zhao, Jun Li, Wenbo Guo · 发表于：Annals of Translational Medicine · 年份：2021 · DOI：10.21037/atm-21-4227 · 被引用次数：21 · 研究领域：Cancer Immunotherapy and Biomarkers、Cancer Genomics and Diagnostics、Colorectal Cancer Treatments and Studies

BACKGROUND: Tumor mutational burden (TMB) is emerging as a promising biomarker in immune checkpoint inhibitor (ICI) therapy. Despite whole-exome sequencing (WES) being the gold standard for quantifying TMB, TMB is determined by selected targeted panels in most cases, and WES-derived TMB data are lacking due to the greater cost and complexity. Determining TMB thresholds is another issue that needs attention. METHODS: A total of 309 patients who had received ICI therapy, representing five cancers (listed in "Results"), were recruited. Among them, 269 patients were evaluable for survival analysis. Tumor and matched blood samples from the patients were analyzed using WES and somatic mutations were determined. TMB is defined as the total number of somatic nonsynonymous mutations in the tumor exome in our study. The patients were divided into different TMB subgroups according to a common fixed number (10 mutations/Mb) or the top tertile within each tumor type. RESULTS: The distribution of WES-derived median TMBs was highly variable across different tumor types, ranging from 2.71 (cholangiocarcinoma) to 2.97 (nervous system tumor), 3.69 (gastric cancer), 4.31 (hepatocellular carcinoma), and 4.64 [colorectal cancer (CRC)] mutations/Mb. In CRC, the survival benefit of TMB-high patients was significant using both the top tertile and the 10 mutations/Mb threshold. In hepatocellular carcinoma, the 10 mutations/Mb threshold showed an advantage over the top tertile threshold. Among patient...