Constructing an APOBEC-related gene signature with predictive value in the overall survival and therapeutic sensitivity in lung adenocarcinoma

Yu Luo; Huiru Wang; Jian Zhong; Jianrong Shi; Xianlin Zhang; Yanni Yang; Ruixin Wu

doi:10.1016/j.heliyon.2023.e21336

Constructing an APOBEC-related gene signature with predictive value in the overall survival and therapeutic sensitivity in lung adenocarcinoma

Heliyon. 2023 Oct 28;9(11):e21336. doi: 10.1016/j.heliyon.2023.e21336. eCollection 2023 Nov.

Authors

Yu Luo^{1

2}, Huiru Wang³, Jian Zhong⁴, Jianrong Shi⁵, Xianlin Zhang⁶, Yanni Yang⁷, Ruixin Wu⁵

Affiliations

¹ Gynecology Department of Jingmen Traditional Chinese Medicine Hospital, Jingmen, 448000, China.
² Beijing University of Traditional Chinese Medicine Guoyitang Expert Clinic, National Medical Hall of Beijing University of Traditional Chinese Medicine, Jingmen Traditional Chinese Medicine Hospital, Jingmen, 448000, China.
³ Clinical College of Traditional Chinese Medicine, Hubei University of Traditional Chinese Medicine, Wuhan, 430014, China.
⁴ Department of Nephrology, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100105, China.
⁵ School of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
⁶ Department of Endocrinology, Wuhan Hospital of Traditional Chinese Medicine, Wuhan Traditional Chinese Medicine Hospital, Wuhan, 430014, China.
⁷ Health Management Center of Jingmen Traditional Chinese Medicine Hospital, Jingmen, 448000, China.

Abstract

Background: APOBEC family play an important role in cancer mutagenesis and tumor development. The role of APOBEC family in lung adenocarcinoma (LUAD) has not been studied comprehensively.

Materials and methods: The expression data of pan-cancer as well as LUAD was obtained from public databases. The expression level of APOBEC family genes was analyzed in different normal and cancer tissues. APOBEC mutagenesis enrichment score (AMES) was utilized to evaluate the APOBEC-induced mutations and the relation of APOBEC with genomic instability. Gene set enrichment analysis was used to identify differentially enriched pathways. Univariate Cox regression and Lasso regression were applied to screen key prognostic genes. The immune cell infiltration was estimated by CIBERSORT. RT-qPCR assay, CCK-8 and Transwell assay were conducted to explore gene expression and lung cancer cell invasion.

Results: Cancer tissues had significantly altered expression of APOBEC family genes and the expression patterns of APOBEC family were different in different cancer types. APOBEC3B was the most aberrantly expressed in most cancer types. In LUAD, we observed a significantly positive correlation of AMES with intratumor heterogeneity (ITH), tumor neoantigen burden (TNB), and tumor mutation burden (TMB). High AMES group had high mutation counts of DNA damage repair pathways, and high enrichment of cell cycle and DNA repair pathways. We identified four prognostic genes (LYPD3, ANLN, MUC5B, and FOSL1) based on AMES, and constructed an AMES-related gene signature. The expressions of four genes were enhanced and accelerated the invasion ability and viability of lung cancer cells. Furthermore, we found that high group increased oxidative stress level.

Conclusions: APOBEC family was associated with genomic instability, DNA damage-related pathways, and cell cycle in LUAD. The AMES-related gene signature had a great potential to indicate the prognosis and guide immunotherapy/chemotherapy for patients suffering from LUAD.

Keywords: APOBEC family; APOBEC mutagenesis enrichment score; Genomic instability; Immunotherapy; Lung adenocarcinoma; Oxidative stress; Prognostic signature.