Bioinformatic analysis of the prognostic value and potential regulatory network of FOXF1 in papillary thyroid cancer

Abstract

FOXF1 belongs to the forkhead family of transcription factors. In this study, we aimed to explore the expression profile of FOXF1 in papillary thyroid cancer (PTC) and corresponding adjacent normal tissues, by using data from The Cancer Genome Atlas‐Thyroid Cancer (TCGA‐THCA) and The Genotype‐Tissue Expression (GTEx) project. Also, we studied its prognostic significance in PTC and its potential regulatory network. Results showed that FOXF1 expression was significantly lower in PTC tissues compared with adjacent normal tissues. Subgroup analysis only confirmed the downregulation in classical histological variant, but not in tall‐cell and follicular variants. FOXF1 downregulation was associated with advanced T stages, positive nodal invasion, and advanced pathological stages of the classical variants. FOXF1 expression might be a fair prognostic marker in terms of recurrence, which independently predicted favorable RFS (HR:0.114, 95%CI: 0.045–0.289, p < .001). We examined FOXF1 somatic mutations, gene‐level copy number alterations (CNAs) and the methylation status of 57 CpG sites in more than 350 classical PTC cases. However, no expression‐related genetic and epigenetic alterations were identified. Based on 20,048 genes with RNA‐seq data, we identified 16 genes that showed strongly positive co‐expression (Pearson's r ≥ 0.6) with FOXF1. Available evidence showed that some of the genes have well‐characterized tumor suppressive effects. We hypothesized that some of these genes might be the upstream regulators or downstream effectors of FOXF1 in classical PTC. In conclusion, FOXF1 mRNA was typically downregulated in classical PTC. Its expression might be a specific and independent prognostic biomarker in terms of RFS in classical PTC patients.

GADD45B Transcript Is a Prognostic Marker in Papillary Thyroid Carcinoma Patients Treated With Total Thyroidectomy and Radioiodine Therapy

“…Gene expression profiling has been widely evaluated in thyroid cancer for biomarker discovery, especially for diagnostic purposes (14)(15)(16)(17). Transcriptomic-based studies have revealed predictors candidates of prognosis, including overexpression of MUC1 (18), MEDAG (19), and SPHK1 (20), and downexpression of FMO1 (21), and FOXF1 (22). Signatures of multigene classifiers were also reported (23,24).…”

Prognostic biomarkers for predicting papillary thyroid carcinoma patients at high risk using nine genes of apoptotic pathway

“…While conventional clinico-pathological factors such as age, stage, extrathyroidal spread and tumour size are significant in the risk stratification of PTC patients, they have their own limitations and are not that efficient. Thus, aided by the development in the high-throughput sequencing methods and availability of a huge amount of experimental data, various molecular prognostic markers have been proposed in the past [5][6][7][8][9][10][11][12][14][15][16]. The understanding of the mechanistic roles of these molecules in the PTC carcinogenesis has initiated a further enquiry into other complicated molecular processes, which may be crucial in PTC progression and development.…”

Prognostic Biomarkers for Predicting Papillary Thyroid Carcinoma Patients at High Risk Using Nine Genes of Apoptotic Pathway

“…While conventional clinico-pathological factors such as age, stage, extrathyroidal spread and tumour size are significant in risk stratification of PTC patients, they have their own limitations and are not that efficient. Thus, aided by the development in the high-throughput sequencing methods and availability of a huge amount of experimental data, various molecular prognostic markers have been proposed in the past (5)(6)(7)(8)(9)(10)(11)(12)(14)(15)(16). The understanding of the mechanistic roles of these molecules in the PTC carcinogenesis has initiated a further enquiry into other complicated molecular processes, which may be crucial in PTC progression and development.…”

“…In the past, several gene expression-based biomarker have been reported that play a crucial role in PTC prognosis; owing to their altered/differential expression profiles. For example FOXF1 (HR:0.114, 95%CI: 0.045-0.289) and FMO1 (HR:0.202; 95% CI: 0.084-0.487) genes were shown to be associated with favourable RFS (recurrence free survival) in PTC patients (8,9). Downregulation of FOXF1, the gene belonging to the forkhead family of TFs (transcription factors), was also seen to be related with advanced T staging, nodal invasion, and late pathological staging.…”