Aberrant S100A16 expression might be an independent prognostic indicator of unfavorable survival in non-small cell lung adenocarcinoma

Abstract

S100A16 is a conserved member of the S100 protein family in mammals. Its upregulation was observed in many tumors and is related to malignant transformation. In this study, we explored the independent prognostic value of S100A16 in terms of overall survival (OS) and recurrence-free survival (RFS) by performing a retrospective study, using data in The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD). Besides, by using deep sequencing data in TCGA-LUAD, we also explored the association between S100A16 expression and its DNA methylation and copy number alterations (CNAs). Results showed that the primary LUAD tissues (N = 514) had significantly elevated S100A16 expression compared with the normal lung tissues (N = 59). Based on OS data of 502 primary LUAD cases, we found that high S100A16 expression was correlated with inferior OS. The following univariate and multivariate analysis confirmed that increased S100A16 expression was an independent prognostic indicator of unfavorable OS (HR: 1.197, 95%CI: 1.050-1.364, p = 0.007) and RFS (HR: 1.206, 95%CI: 1.045-1.393, p = 0.011). By examining the DNA methylation data in TCGA-LUAD, we found that some S100A16 DNA CpG sites were generally hypermethylated in normal tissues, but not in LUAD tissues. Regression analysis identified a moderately negative correlation between S100A16 expression and its DNA methylation. In comparison, although DNA amplification (+1/+2) was frequent (378/511, 74%) in LUAD patients, it was not associated with increased S100A16 expression. Based on findings above, we infer that aberrant S100A16 expression might be modulated by its DNA hypomethylation and serves as an independent prognostic indicator of unfavorable OS and RFS in LUAD.

Fig 1. LUAD tissues had significantly elevated S100A16 expression compared with normal lung tissues.

A-B. Heatmap (A) and plots chart (B) showing S100A16 RNA expression in LUAD tissues (N = 514) and in normal lung tissues (N = 59). C-D. S100A16 IHC staining images. C: Normal lung (left) and bronchus (right). D: LUAD tissues. Image credit: Human Protein Atlas. Images were obtained from: v18.proteinatlas.org, via: http://www.proteinatlas.org/ENSG00000188643-S100A16/tissue/lung#img http://www.proteinatlas.org/ENSG00000188643-S100A16/tissue/bronchus#img http://www.proteinatlas.org/ENSG00000188643-S100A16/pathology/tissue/lung+cancer#img.

Fig 2. Comparison of S100A16 expression between the groups with different clinicopathological parameters.

A-C. Plots chart of S100A16 expression between the living and dead cases (A), between the cases with or without nodal invasion (B) and between the patients with or without recurrence (C).

Fig 3. The association between S100A16 expression and OS and RFS in LUAD patients.

A-B. Kaplan-Meier curves of OS (A) and RFS (B) in LUAD patients, by using data from TCGA-LUAD. C-D. Kaplan-Meier curves of OS (C) and FPS (D) in LUAD patients. Results were generated by using Kaplan-Meier Plotter. Patients were grouped by the median S100A6 expression.

Fig 4

The correlation between S100A16 expression and its DNA methylation in LUAD tissues. A. Heatmap of the correlation between S100A16 expression and its DNA methylation. B-C. Regression analysis of the correlation between S100A16 expression and the average methylation of all CpG sites in the array (B) or the selected 8 CpG sites (C).

Fig 5

The correlation between S100A16 expression and its DNA methylation in 53 LUAD cell lines. Regression analysis of the correlation between S100A16 expression and its DNA methylation in 53 LUAD cell lines. RRBS: Reduced representation bisulfite sequencing.

Fig 6. The association between S100A16 expression and its CNAs.

A-B. Heatmap (A) and plots chart (B) of S100A16 DNA CNAs and its RNA expression. -2: homozygous deletion; -1: heterozygous loss, 0: copy-neutral; +1: low-level copy gain; +2: high-level amplification.