Growth differentiation factor 15 (GDF15): a new biomarker for medullary thyroid cancer patients

Background: Growth Differentiation Factor 15 (GDF15) is a stress-induced cytokine that has been proposed as a biomarker in various cancers, with levels increasing alongside disease progression. GDF15 exerts its effects through binding to the GDNF family receptor α-like (GFRAL) and the ret receptor that is encoded by RET oncogene whose activation is primarily responsible of medullary thyroid cancer (MTC). We aimed to assess the protein and mRNA expression of GDF15 in MTC and their relationship with the disease status. Methods: Serum GDF15 levels were measured by ELISA in 161 patients with sporadic MTC and 47 normal control subjects. Associations between serum GDF15 levels and gender, body mass index (BMI), calcitonin (Ct), carcinoembryonic antigen (CEA), disease status, disease progression, and overall survival were analyzed. Dynamic changes in GDF15 levels were evaluated in patients submitted to systemic therapies. GDF15 mRNA expression was assessed in 96 formalin-fixed paraffinembedded (FFPE) MTC samples using Nanostring technology. Results: Serum GDF15 levels were significantly higher in MTC patients compared to control subjects. They were more elevated in male and older patients, but no association with BMI was found. After adjusting for age and gender, GDF15 levels correlated with serum Ct and CEA levels. Elevated GDF15 levels were associated with more advanced disease status, but not with disease progression according to RECIST 1.1. Higher GDF15 levels predicted poorer overall survival in the entire cohort, in patients with metastatic disease and in patients submitted to systemic therapy. A significant decrease in GDF15 levels was observed in patients submitted to systemic therapy. Higher serum GDF15 levels were found in RET-mutant cases. At the transcriptomic level, metastatic MTC samples showed increased GDF15 mRNA expression. Positive correlation was found between GDF15 intratumoral mRNA and serum protein levels. By Nanostring assay, GDF15 mRNA expression was associated mRNA expression of relevant genes involved in myogenesis, angiogenesis, and epithelial–mesenchymal transition in MTC. Conclusions: GDF15 might serve as a novel prognostic biomarker in MTC,associated with disease severity and survival. Given its signaling through the RET pathway, GDF15 could represent a relevant therapeutic and biological target in RETdriven MTC.