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. 2020 Apr 30:11:269.
doi: 10.3389/fendo.2020.00269. eCollection 2020.

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

Mateus C Barros-Filho  1 , Julia B H de Mello  1 , Fabio A Marchi  1 , Clóvis A L Pinto  2 , Igor C da Silva  3 , Patricia K F Damasceno  4 , Milena B P Soares  4   5 , Luiz P Kowalski  6 , Silvia R Rogatto  7
Affiliations

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

Mateus C Barros-Filho et al. Front Endocrinol (Lausanne). .

Abstract

Currently, there is a lack of efficient recurrence prediction methods for papillary thyroid carcinoma (PTC). In this study, we enrolled 202 PTC patients submitted to total thyroidectomy and radioiodine therapy with long-term follow-up (median = 10.7 years). The patients were classified as having favorable clinical outcome (PTC-FCO, no disease in the follow-up) or recurrence (PTC-RE). Alterations in BRAF, RAS, RET, and TERT were investigated (n = 202) and the transcriptome of 48 PTC (>10 years of follow-up) samples was profiled. Although no mutation was associated with the recurrence risk, 68 genes were found as differentially expressed in PTC-RE compared to PTC-FCO. Pathway analysis highlighted a potential role of cancer-related pathways, including signal transduction and FoxO signaling. Among the eight selected genes evaluated by RT-qPCR, SLC2A4 and GADD45B showed down-expression exclusively in the PTC-FCO group compared to non-neoplastic tissues (NT). Increased expression of GADD45B was an independent marker of shorter disease-free survival [hazard ratio (HR) 2.9; 95% confidence interval (CI95) 1.2-7.0] in our cohort and with overall survival in the TCGA dataset (HR = 4.38, CI95 1.2-15.5). In conclusion, GADD45B transcript was identified as a novel prognostic marker candidate in PTC patients treated with total thyroidectomy and radioiodine therapy.

Keywords: BRAF mutation; GADD45B; TERT promoter mutation; papillary thyroid cancer; prognostic markers; transcription profiling.

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Figures

Figure 1
Figure 1
Supervised hierarchical clustering analysis comprising 61 genes differentially expressed in primary PTC-RE compared to PTC-FCO (samples in columns and genes in rows). Two major groups are shown: the first (gray) is enriched by patients with favorable clinical outcomes and the second (black) by patients who relapsed in the follow-up.
Figure 2
Figure 2
Expression levels of eight genes evaluated by RT-qPCR (TLDA custom assay) in PTC samples previously investigated by microarray analysis (yellow dots) and in an array-independent set of samples (blue dots). GADD45B showed statistically significant higher expression levels in PTC-RE compared to PTC-FCO cases. FCO, favorable clinical outcome; RE, recurrence; ***P < 0.001; **P < 0.01; *P < 0.05; NS, not significant (Tukey post-hoc test).
Figure 3
Figure 3
Survival analysis performed according to the GADD45B expression levels. (A) Kaplan–Meier plot demonstrating shorter disease-free survival in patients presenting higher GADD45B expression levels (above median) evaluated by RT-qPCR. (B) Kaplan–Meier plot showing a shorter overall survival in cases presenting higher GADD45B expression in PTC patients from the TCGA database (RNA sequencing). P-values were obtained by Cox proportional-hazards regression, and median expression was used as a cut-off.
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