A pan-cancer analysis unveiling the function of NR4A family genes in tumor immune microenvironment, prognosis, and drug response.

BACKGROUND: NR4A family genes play crucial roles in cancers. However, the role of NR4A family genes in cancers remains paradoxical as they promote or suppress tumorigenesis. OBJECTIVE: We aimed to conduct comprehensive analyses of the association between the expression of NR4A family genes and tumor microenvironment (TME) based on bioinformatics methods. METHODS: We collected RNA-seq data from 33 cancer types and 20 normal tissue sites from the TCGA and GTEx databases. Expression patterns of NR4A family genes and their associations with DNA methylation, miRNA, overall survival, drug responses, and tumor microenvironment were investigated. RESULTS: Significant downregulation of all NR4A family genes was observed in 15 cancer types. DNA promoter methylation and expression of NR4A family genes were negatively correlated in five cancers. The expression of 10 miRNAs targeting NR4A family genes was negatively correlated with the expression of NR4A family genes. High expression of all NR4A family genes was associated with poor prognosis in stomach adenocarcinoma and increased expressions of NR4A2 and NR4A3 were associated with poor prognosis in adrenocortical carcinoma. In addition, we found an elevated expression of NR4A2, which enhances the response to various chemotherapeutic drugs, whereas NR4A3 decreases drug sensitivity. Interestingly, in breast cancer, NR4A3 was significantly associated with C2 (IFN-γ dominant), C3 (inflammatory), and C6 (TGF-ß dominant) immune subtypes and infiltrated immune cell types, implying both oncogenic and tumor-suppressive functions of NR4A3 in breast cancer. CONCLUSION: The NR4A family genes have the potential to serve as a diagnostic, prognostic, and immunological marker of human cancers.

MGMT Methylation Is Associated with Human Papillomavirus Infection in Cervical Dysplasia: A Longitudinal Study.

Cervical premalignancy/malignancy, as detected by cervical cytology or biopsy, can develop as a result of human papillomavirus (HPV) infection. Meanwhile, DNA methylation is known to be associated with carcinogenesis. In this study, we thus attempted to identify the association between MGMT methylation and persistent HPV infection using an Epi-TOP MPP assay. Integrative analysis of DNA methylation was carried out here using longitudinal cervical cytology samples of seven patients with atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (ASC-US/LSIL). Then, a gene expression analysis using the longitudinal cervical cytology samples and a public database (The Cancer Genome Atlas (TCGA)) was performed. Upon comparing the ASC-US or LSIL samples at the 1st collection and the paired samples at the 2nd collection more than 6 months later, we found that they became hypermethylated over time. Then, using the longitudinal data, we found that the MGMT methylation was associated with HPV infection. Moreover, TCGA dataset revealed an association between downregulated MGMT mRNA expression and poor overall survival. This decreased MGMT mRNA expression was observed to have an inverse relationship with MGMT methylation levels. In this study, we found that the MGMT methylation level could potentially serve as a valuable prognostic indicator for the transition from ASC-US/LSIL to cervical cancer.

Shallow Whole-Genome Sequencing of Cell-Free DNA (cfDNA) Detects Epithelial Ovarian Cancer and Predicts Patient Prognosis.

Despite the progress in diagnostics and therapeutics, epithelial ovarian cancer (EOC) remains a fatal disease. Using shallow whole-genome sequencing of plasma cell-free DNA (cfDNA), we investigated biomarkers that could detect EOC and predict survival. Plasma cfDNA from 40 EOC patients and 20 healthy subjects were analyzed by shallow whole-genome sequencing (WGS) to identify copy number variations (CNVs) and determine the Z-scores of genes. In addition, we also calculated the genome-wide scores (Gi scores) to quantify chromosomal instability. We found that the Gi scores could distinguish EOC patients from healthy subjects and identify various EOC histological subtypes (e.g., high-grade serous carcinoma). In addition, we characterized EOC CNVs and demonstrated a relationship between RAB25 amplification (alone or with CA125), and disease-free survival and overall survival. This study identified RAB25 amplification as a predictor of EOC patient survival. Moreover, we showed that Gi scores could detect EOC. These data demonstrated that cfDNA, detected by shallow WGS, represented a potential tool for diagnosing EOC and predicting its prognosis.

N-terminal pro-brain natriuretic peptide levels predict left ventricular systolic function in patients with chronic kidney disease.

N-terminal pro-brain natriuretic peptide (NT-proBNP) can be a useful marker for left ventricular (LV) dysfunction in patients without kidney disease. This study was conducted to clarify the relationship between NT-proBNP and LV systolic function in patients with decreased renal function. We studied 256 chronic kidney disease (CKD) patients, patients on dialysis were excluded. The median glomerular filtration rate was 24 (13-36) mL/min/1.73 m(2) and the median NT-proBNP was 4,849 (1,310-19,009) pg/mL. The prevalence of LV systolic dysfunction increased from the lower to the upper NT-proBNP quartiles (I, 17%; II, 34%; III, 61%; and IV, 72%; p<0.001 for trend). The NT-proBNP quartile was an independent predictor of LV systolic dysfunction after adjustment for renal function, compared with quartile I: II, odds ratio (OR) 3.99 (95% confidence interval [CI],1.34-11.93); III, OR 11.28 (95% CI, 3.74-33.95); and IV, OR 36.97 (95% CI, 11.47-119.1). Area under the curve and optimum cut points for NT-proBNP to detect LV systolic dysfunction were 0.781 and 2,165 pg/mL in CKD stage 3, 0.812 and 4,740 pg/mL in CKD stage 4, and 0.745 and 15,892 pg/mL in CKD stage 5. The NT-proBNP level was a predictor of LV systolic dysfunction in CKD patients. Optimum cut points should be stratified according to renal function.