The Tumor Mutational Burden of Chinese Advanced Cancer Patients Estimated by a 381-cancer-gene Panel

Wu Zhuang; Junxun Ma; Xudong Chen; Guoqiang Wang; Jing Lu; Yanan Chen; Hua Dong; Shangli Cai; Yuzi Zhang; Xiaochen Zhao; Youcai Zhu; Chunwei Xu; Yunjian Huang; Zhangzhou Huang; Xiaofeng Zhu; Hong Jiang; Zhijie Wang

doi:10.7150/jca.24932

The Tumor Mutational Burden of Chinese Advanced Cancer Patients Estimated by a 381-cancer-gene Panel

J Cancer. 2018 Jun 6;9(13):2302-2307. doi: 10.7150/jca.24932. eCollection 2018.

Authors

Wu Zhuang¹, Junxun Ma², Xudong Chen³, Guoqiang Wang⁴, Jing Lu⁵, Yanan Chen⁵, Hua Dong⁵, Shangli Cai⁴, Yuzi Zhang⁴, Xiaochen Zhao⁴, Youcai Zhu⁶, Chunwei Xu⁷, Yunjian Huang¹, Zhangzhou Huang¹, Xiaofeng Zhu⁸, Hong Jiang⁹, Zhijie Wang¹⁰

Affiliations

¹ Department of Medical Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fujian, P.R. China.
² Department of Oncology, Chinese PLA General Hospital, Beijing, P.R. China.
³ Department of Interventional Radiology, the Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, P.R. China.
⁴ The medical department, 3D Medicine Inc. Shanghai, P.R. China.
⁵ The bioinformatics department, 3D Medicine Inc. Shanghai, P.R. China.
⁶ Department of Thoracic Disease Center, Zhejiang Rongjun Hospital, Zhejiang, P.R. China.
⁷ Department of Pathology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fujian, P.R. China.
⁸ Transplantation Center, Department of Transplant Surgery, The First Affiliated Hospital, Sun Yet-sen University, Guangzhou, P. R. China.
⁹ Oncology Department, East Hospital Affiliated to Shanghai Tongji University, Shanghai, P.R. China.
¹⁰ Department of medical oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, P.R. China.

Abstract

Purpose: Tumor mutational burden (TMB) calculated by whole-exome sequencing (WES) is proved to be effective to predict the clinical benefit of immune checkpoint blockades. However, WES is not commonly used in China. We aimed to determine if a 381-caner-gene panel (CGP) could be used to estimate TMB, delineate the landscape of TMB of Chinese patients and identify mutated genes and pathways related to higher TMB. Methods: We first evaluated the correlation between the TMB estimated by a 381-cancer-gene panel MasterView and WES using the data from the melanoma sample cohort. 3023 formalin fixed, paraffin-embedded tumor specimens from 2932 Chinese patients with advanced solid tumor were profiled for 381 gene sequencing, the baits of which covered 4,557 exons of 365 cancer-related genes and 47 introns of 25 genes frequently rearranged in cancer (All performed in a lab who achieved full marks five times in the external quality assessment by College of American Pathologists [CAP]). Using the sequencing data, we estimated the TMB of Chinese advanced solid tumor and identified mutated genes and pathways related to higher TMB level. Results: 381-CGP-mutational burden was strongly associated with those calculated by WES (R² = 0.978). The median TMB for each tumor type was 5.65 (colorectal cancer), 4.84 (lung cancer), 4.03 (hepatobiliary cancer), 4.03 (gastric carcinoma), 4.03 (breast cancer) mutations/mb respectively. No correlation was observed between TMB level and age (P = 0.577) or gender (P = 0.307). The TMB of patients with mismatch repair (MMR) or DNA repair response (DDR) pathway deficiency was significantly higher than that without MMR or DDR pathway deficiency (P < 0.001). Conclusion: The 381-cancer gene panel is a clinical practicable method to assess tumor mutational burden compared with whole exome sequencing. MMR and DDR deficiency are correlated with higher tumor mutational burden of Chinese patients with advanced solid tumors.

Keywords: DNA damage response; Tumor mutational burden; cancer-gene panel; mismatch repair.