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

Chuang Zhou; Song Chen; Fei Xu; Jinwang Wei; Xiaoyu Zhou; Zhiqiang Wu; Longshuan Zhao; Jun Liu; Wenbo Guo

doi:10.21037/atm-21-4227

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

Ann Transl Med. 2021 Sep;9(18):1437. doi: 10.21037/atm-21-4227.

Authors

Chuang Zhou¹, Song Chen², Fei Xu³, Jinwang Wei³, Xiaoyu Zhou³, Zhiqiang Wu², Longshuan Zhao¹, Jun Liu³, Wenbo Guo²

Affiliations

¹ Department of Hepatobiliary Pancreatic Surgery, the First Afﬁliated Hospital of Zhengzhou University, Zhengzhou, China.
² Department of Radiation Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
³ Genomicare Biotechnology (Shanghai) Co., Ltd., Shanghai, China.

Abstract

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 patients with nervous system tumors, cholangiocarcinoma, and gastric cancer, no obvious survival differences were observed between the TMB-high and TMB-low groups with either TMB stratification approach.

Conclusions: The TMB threshold criterion may vary for different cancers. Our data suggest that TMB is unable to predict ICI benefit across all cancer types in Chinese patients. However, it may be an effective biomarker for predicting the clinical benefit of ICI therapy for patients with CRC.

Keywords: Tumor mutational burden (TMB); immunotherapy; whole-exome sequencing (WES).