Tumor mutation burden determined by a 645-cancer gene panel and compared with microsatellite instability and mismatch repair genes in colorectal cancer

Zhaofei Zhou; Kang Li; Qiang Wei; Lingxiang Chen; You Shuai; Yajing Wang; Kang He; Lixiang Si; Yuejiao Zhong; Jianwei Lu

doi:10.21037/jgo-21-572

Tumor mutation burden determined by a 645-cancer gene panel and compared with microsatellite instability and mismatch repair genes in colorectal cancer

J Gastrointest Oncol. 2021 Dec;12(6):2775-2787. doi: 10.21037/jgo-21-572.

Authors

Zhaofei Zhou¹, Kang Li², Qiang Wei², Lingxiang Chen¹, You Shuai¹, Yajing Wang¹, Kang He¹, Lixiang Si¹, Yuejiao Zhong¹, Jianwei Lu¹

Affiliations

¹ Department of Medical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
² Department of Radiology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.

Abstract

Background: Tumor mutation burden (TMB) assessed by tumor-related gene panels (CRGP), microsatellite instability (MSI), and mismatch repair (MMR) has been proven to be associated with prognosis, and these factors are prognostic indicators in predicting the benefits of immune checkpoint blockade (ICB) in solid tumors. However, whether the TMB calculated by CRGPs, MSI, and MMR is associated with overall survival (OS) in patients with colorectal cancer (CRC) remains to be explored.

Methods: The prognostic threshold of the panel-TMB was explored by a panel of 645 genes (GP645) from 41 CRC patients in Jiangsu Cancer Hospital (JCH dataset). The results were further validated using 531 CRC patients from The Cancer Genome Atlas (TCGA) database.

Results: Mutations of the GP645 genes were distributed on 21 chromosomes. Spearman correlation analysis showed that the panel-TMB was positively correlated with TMB measured by whole-exome sequencing (WES) (wTMB) in the TCGA dataset (R=0.75, P<0.001). Kaplan-Meier survival analysis demonstrated that higher panel-TMB in CRC patients was significantly associated with a poor OS (P=0.0062). MSI and MMR status were determined using the GP645 by next-generation sequencing (NGS). The proportions of MSI-H and dMMR accounted for less than 10% in CRC, the vast majority of MSI-H/dMMR samples also had high TMB [positive predictive value (PPV) =66.6%], and only 13.3% of samples with high TMB were classified as MSI-high/dMMR. In addition, patients with low-TMB were associated with MSS/pMMR (96.2%), and these results are consistent with earlier studies.

Conclusions: GP645 was constructed to evaluate OS in Chinese CRC patients. Panel-TMB and MSI/MMR might be potential prognostic predictors of CRC patients using the GP645.

Keywords: Tumor mutation burden (TMB); colorectal cancer (CRC); gene panel; microsatellite instability (MSI); mismatch repair (MMR).