Oral Presentation ESA-SRB-NZSE-CaSR 2026 in conjunction with ENSA

Circulating GDF-15 as a Biomarker of Activity in Oncocytic Thyroid Cancer (141617)

Stephen Ludgate 1 2 , Martyn Bullock 3 , Mark Ridgwell 4 , Sarah C Brennan 1 5 , Christopher Barnes 6 , Venessa HM Tsang 1 3 5 , Bruce G Robinson 1 3 5 , Matti L Gild 1 3 5 , Roderick J Clifton-Bligh 1 3 5
  1. The Department of Diabetes, Metabolism and Endocrinology, Royal North Shore Hospital, St Leonards, NSW, Australia
  2. The School of Medicine, Trinity College Dublin, The University of Dublin, Dublin, Ireland
  3. Kolling Institute of Medical Research, St Leonards, NSW, Australia
  4. NSW Health Pathology, St Leonards, NSW, Australia
  5. Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia
  6. Department of Endocrine Surgery, Royal North Shore Hospital, St Leonards, NSW, Australia

Oncocytic thyroid carcinoma (OTC) is characterised by mitochondrial complex I dysfunction, radioactive iodine resistance, and reduced survival compared to other differentiated thyroid cancers. Growth differentiation factor 15 (GDF-15) is a stress-induced mitokine upregulated by complex I dysfunction via the integrated stress response, with roles in remodelling of the tumour microenvironment and cancer-associated cachexia. We measured serum GDF-15 in patients with thyroid cancer and assessed its association with OTC, disease status and multi-kinase inhibitor (MKI) therapy.

GDF-15 was measured in 51 patients with thyroid cancer. Primary analyses included 10 OTC, 35 papillary (PTC) and six follicular thyroid carcinoma (FTC). Patients were stratified by disease activity and concurrent MKI therapy. Multivariable linear regression was performed with log₁₀(GDF-15) as the outcome. Bulk RNA sequencing data from OTC and pan-cancer data from TCGA were analysed for correlations between GDF15 expression, immune-related signatures, and thyroid differentiation markers.

Serum GDF-15 differed significantly across OTC, PTC, and FTC (p=0.025). In OTC patients with active disease and no concurrent MKI, GDF-15 was significantly higher (median 15,535 ng/L) than in PTC patients with equivalent disease status (median 860 ng/L; p=0.007). Concurrent MKI was associated with lower GDF-15 in OTC, comparable to patients without active disease. In multivariable analysis restricted to active disease patients not receiving concurrent MKI (n=16), OTC subtype was the dominant independent predictor of serum GDF-15, associated with an 8.54-fold higher level than PTC (95% CI 3.38–21.57; p<0.001). Transcriptomic analysis showed GDF15 expression in OTC was inversely correlated with thyroid differentiation score and NIS expression and positively with immune checkpoint and interferon-γ signatures.

Serum GDF-15 is elevated in OTC, consistent with mitochondrial complex I dysfunction, and is profoundly and subtype-specifically suppressed by MKI therapy, independent of disease activity. These findings establish a rationale for investigating GDF-15-mediated immune exclusion as a mechanism of therapeutic resistance in OTC.