Identification of an Individualized Metabolism Prognostic Signature and Related Therapy Regimens in Early Stage Lung Adenocarcinoma

Junjie Hu; Huansha Yu; Liangdong Sun; Yilv Yan; Lele Zhang; Gening Jiang; Peng Zhang

doi:10.3389/fonc.2021.650853

Identification of an Individualized Metabolism Prognostic Signature and Related Therapy Regimens in Early Stage Lung Adenocarcinoma

Front Oncol. 2021 Apr 28:11:650853. doi: 10.3389/fonc.2021.650853. eCollection 2021.

Authors

Junjie Hu¹, Huansha Yu², Liangdong Sun¹, Yilv Yan¹, Lele Zhang³, Gening Jiang¹, Peng Zhang¹

Affiliations

¹ Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
² Experimental Animal Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
³ Central Laboratory of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

Objective: The choice of adjuvant therapy for early stage lung adenocarcinoma (LUAD) remains controversial. Identifying the metabolism characteristics leading to worse prognosis may have clinical utility in offering adjuvant therapy.

Methods: The gene expression profiles of LUAD were collected from 22 public datasets. The patients were divided into a meta-training cohort (n = 790), meta-testing cohort (n = 716), and three independent validation cohorts (n = 345, 358, and 321). A metabolism-related gene pair index (MRGPI) was trained and validated in the cohorts. Subgroup analyses regarding tumor stage and adjuvant chemotherapy (ACT) were performed. To explore potential therapeutic targets, we performed in silico analysis of the MRGPI.

Results: Through machine learning, MRGPI consisting of 12 metabolism-related gene pairs was constructed. MRGPI robustly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I or II disease in all cohorts. Multivariable analysis confirmed that MRGPI was an independent prognostic factor. ACT could not improve prognosis in high-risk patients with stage I disease, but could improve prognosis in the high-risk patients with stage II disease. In silico analysis indicated that B3GNT3 (overexpressed in high-risk patients) and HSD17B6 (down-expressed in high-risk patients) may make synergic reaction in immune evasion by the PD-1/PD-L1 pathway. When integrated with clinical characteristics, the composite clinical and metabolism signature showed improved prognostic accuracy.

Conclusions: MRGPI could effectively predict prognosis of the patients with early stage LUAD. The patients at high risk may get survival benefit from PD-1/PD-L1 blockade (stage I) or combined with chemotherapy (stage II).

Keywords: adjuvant therapy; early stage; lung adenocarcinoma; metabolism genes; prognostic signature.