IGF2 is a Potential Factor in RAI-refractory Non-medullary Thyroid Cancer

Abstract Background: Non-medullary thyroid cancer (NMTC) is the most frequent endocrine tumor with in most cases a good prognosis after thyroidectomy and 131I radioactive iodide (RAI) ablation. In contrast, 30-40% of patients with metastatic NMTC are unresponsive to 131I RAI treatment as a result of tumor dedifferentiation. Currently, underlying molecular mechanisms of NMTC dedifferentiation still remain elusive and predictive biomarkers are lacking. In the present study we therefore aim to identify molecular biomarkers in primary tumors that are associated with RAI refractoriness. Methods: A retrospective cohort of 63 NMTC patients, including all histological subtypes, was gathered for this study and consisted of RAI-sensitive differentiated NMTC patients (N=35) and RAI-refractory (poorly) differentiated NMTC patients (N=28). RAI sensitivity was defined as the response to RAI of residual disease after primary surgery (persistence and/or progression versus regression). Total DNA and RNA were extracted from archived formalin-fixed paraffin embedded (FFPE) tumor tissues. Extensive intratumoral mutation profiling, gene fusions analysis, TERT promoter mutation analysis and FFPE-compatible RNA sequencing were performed in all patients. In eight NMTC patients, available from an independent cohort, total circulating IGF2 concentrations were determined using ELISA before and after undergoing primary treatment.Results: RAI-refractory NMTC patients were diagnosed at an older age and displayed less favorable TNM staging as compared to RAI-sensitive NMTC patients. Genetic analyses revealed an increased mutational load in RAI-refractory NMTC, including mutations in AKT1, PTEN, TP53 and TERT promoter. Transcriptomic analyses revealed profound differential expression of insulin-like growth factor 2 (IGF2) with up to 100-fold higher expression in RAI-refractory NMTC as compared to RAI-sensitive NMTC cases. By ELISA we found significant lower IGF2 plasma concentrations after surgery and subsequent 131I RAI therapy in patients with NMTC compared to pretreatment baseline. Conclusions: Important clinical, genetic and transcriptomic differences between patients with RAI-sensitive NMTC and RAI-refractory NMTC were identified. Most notably an increased expression of IGF2 in RAI-refractory tumors. Plasma levels of IGF2 decreased post-therapy in NMTC patients from an independent cohort. These findings suggest that the tumor-promoting growth factor IGF2 has a potential role in acquiring RAI refractoriness.