Analysis of Tumour Mutation Burden (TMB) in Chinese Lung Adenocarcinoma: Implications for Clinical Practice

Objectives: Immune checkpoint blockades, such as PD-1/PD-L1 inhibitors, has recently shown remarkable clinical benefit in many types of cancers. Recent studies have revealed that TMB is highly correlated with immunotherapy efficacy. In this study, a method for evaluating TMB using CGP was established. Methods: Detection of TMB using CGP is based on the variant-calling method, which quantitates the specific mutations to calculate TMB. Its accuracy was confirmed by measuring it against data from TCGA and WES data of clinical samples. Detection of TMB by CGP was validated through the sequencing accuracy, CV, and the LOD of tumour purity. The TMB of Chinese lung adenocarcinoma samples were also analysed. Results: In our study, TMB measured by CGP was highly correlated with that measured by WES in 31 clinical tumour samples. The mean TMB was similar between 599 Chinese lung adenocarcinoma samples measured by CGP and 389 TCGA lung adenocarcinoma samples (7.29 vs 7.60 mutations/Mb). The high TMB was significantly correlated with the alteration of several genes, including TP53, KRAS and genes in DDR pathway. However, the low TMB was correlated with EGFR and ALK variations. Notably, we first discovered that the TMB was lower in Chinese early stage lung adenocarcinoma samples. Conclusions: Our study showed that TMB calculated by the CGP and WES was highly correlated. Based on the analysis of clinical samples, TMB was influenced by several gene alterations. The lower TMB might be related to the poor efficacy of mono-immunotherapy in patients with early stage lung adenocarcinoma. Funding sources: This study was supported by National Key R &D Program of China (Grand No.2016YFC1303800) and National Natural Sciences Foundation Key Program (81372260) and (81773056). Conflicts of interest: Jing Lu, Tongfu Xu, Shangli Cai, and Fugen Li are employees of 3D Medicines, Inc. The remaining authors declare that they have no competing interests to disclose. Ethics Approval Statement: This study was approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science & Technology.