From tumor mutational burden to characteristic targets analysis: Identifying the predictive biomarkers and natural product interventions in cancer management

Cun Liu; Yang Yu; Ge Wang; Jingyang Liu; Ruijuan Liu; Lijuan Liu; Xiaoxu Yang; Huayao Li; Chundi Gao; Yi Lu; Jing Zhuang

doi:10.3389/fnut.2022.989989

From tumor mutational burden to characteristic targets analysis: Identifying the predictive biomarkers and natural product interventions in cancer management

Front Nutr. 2022 Sep 20:9:989989. doi: 10.3389/fnut.2022.989989. eCollection 2022.

Authors

Cun Liu¹, Yang Yu², Ge Wang³, Jingyang Liu⁴, Ruijuan Liu⁵, Lijuan Liu^{5

6}, Xiaoxu Yang⁷, Huayao Li¹, Chundi Gao⁴, Yi Lu^{8

9}, Jing Zhuang⁵

Affiliations

¹ College of Traditional Chinese Medicine, Weifang Medical University, Weifang, China.
² College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
³ Clinical Medical Colleges, Weifang Medical University, Weifang, China.
⁴ First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
⁵ Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China.
⁶ Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, China.
⁷ School of Life Sciences and Technology, Weifang Medical University, Weifang, China.
⁸ Department of Clinical Nutrition, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, China.
⁹ Key Laboratory of Traditional Chinese Medicine Oncology, Zhejiang Cancer Hospital, Hangzhou, China.

Abstract

High-throughput next-generation sequencing (NGS) provides insights into genome-wide mutations and can be used to identify biomarkers for the prediction of immune and targeted responses. A deeper understanding of the molecular biological significance of genetic variation and effective interventions is required and ultimately needs to be associated with clinical benefits. We conducted a retrospective observational study of patients in two cancer cohorts who underwent NGS in a "real-world" setting. The association between differences in tumor mutational burden (TMB) and clinical presentation was evaluated. We aimed to identify several key mutation targets and describe their biological characteristics and potential clinical value. A pan-cancer dataset was downloaded as a verification set for further analysis and summary. Natural product screening for the targeted intervention of key markers was also achieved. The majority of tumor patients were younger adult males with advanced cancer. The gene identified with the highest mutation rate was TP53, followed by PIK3CA, EGFR, and LRP1B. The association of TMB (0-103.7 muts/Mb) with various clinical subgroups was determined. More frequent mutations, such as in LRP1B, as well as higher levels of ferritin and neuron-specific enolase, led to higher TMB levels. Further analysis of the key targets, LRP1B and APC, was performed, and mutations in LRP1B led to better immune benefits compared to APC. APC, one of the most frequently mutated genes in gastrointestinal tumors, was further investigated, and the potential interventions by cochinchinone B and rottlerin were clarified. In summary, based on the analysis of the characteristics of gene mutations in the "real world," we obtained the potential association indicators of TMB, found the key signatures LRP1B and APC, and further described their biological significance and potential interventions.

Keywords: APC; LRP1B; next-generation sequencing; targeted therapy and immunotherapy; tumor mutation burden.