Radioiodine therapy of differentiated thyroid cancer is effective and possibly curative in patients with metastatic lesions that retain iodine avidity. However, in clinical practice, iodine avidity in any metastatic site is usually unknown at the point of initial treatment. Avidity prediction could enable more tailored initial radioiodine treatment. This work aimed to establish the best predictive factors for iodine avidity and subsequent treatment response. Thirty-one patients with metastatic or recurrent thyroid cancer sites in which iodine avidity could be assessed by image-based analysis were included. In tissue specimens from primary surgery, immunohistochemical expression of thyroglobulin (Tg), thyroid peroxidase (TPO), sodium-iodide symporter (NIS) and Ki67, and mutational status of BRAF, RAS and the TERT promoter was analyzed. Biochemical and structural response were assessed by serum Tg response and radiological evaluation. High-risk histology (widely invasive follicular, tall cell subtype papillary, differentiated high-grade or poorly differentiated thyroid carcinoma) combined with expression of TPO, Tg and cytoplasmic NIS performed well in predicting treatment response and iodine avidity. Approximately half of the variation between patients was explained by those variables, outperforming pT stage and mutational status. TPO and Tg expression were the largest contributors in prediction modelling. Radioiodine treatment response and iodine avidity in thyroid cancer can be predicted from histopathological analysis of the primary tumor. High-risk histology and expression of TPO, Tg and NIS were robust and informative predictors. This may be used to adapt treatment strategy in adjuvant and metastatic therapy settings.
Thyroid cancer, the most frequent endocrine tumor, has a good prognosis. However, the survival rate of patients with recurrent or metastatic forms that become resistant to conventional treatments, drops to less than 20% at 10 years, with a mean life expectancy of 3-5 years. The molecular mechanisms that drive the advancement of these forms are still largely unknown, and, therefore, the identification of disease progression biomarkers is of great clinical relevance. Dickkopf-1 (DKK1) is a regulator of the Wnt signaling cascade that controls several biological processes including cell proliferation, differentiation and migration. DKK1 has been associated with progression and poor prognosis in different types of tumors; however, its role in thyroid cancer is still not well defined, and a better characterization is needed. The present study investigated the role of DKK1 in the growth of papillary and follicular thyroid cancers, in in vitro and in vivo models. In vitro, DKK1 silencing, through siRNA, and deletion, via CRISPR/Cas9 editing, were performed in different papillary and follicular thyroid cancer cell lines. Both silencing and deletion reduced cell growth and migration, with the involvement of β-catenin-dependent Wnt and PI3K/mTOR pathways. In vivo xenograft tumor models, DKK1 deletion reduced tumor growth. In conclusion, our findings support the key role of DKK1 in the growth of differentiated thyroid cancers both in vitro and in vivo.
Although uncommon, thyroid nodules (TN) in pediatric and young adult patients carry higher malignancy risk and often present with a high burden of metastatic disease than adults. The molecular features underlying this distinct clinical behavior remain unclear. We analyzed Afirma Genomic Sequencing Classifier (GSC) data from 283,621 TN, comparing patients <21 and ≥21 years. Cytology (Bethesda), GSC benign (B) vs suspicious (S) calls, and Afirma Xpression Atlas (XA) variant/fusion profiles were evaluated in GSC-S and Bethesda V/VI samples. Genome-wide expression was used to derive pathway signatures and thyroid cancer-related scores: BRAF-RAS score (BRS), ERK, follicular and epithelial-to-mesenchymal transition (FMT, EMT) and thyroid differentiation scores (TDS). Among 2,397 patients <21 (median age 18.9; 81.4% female) and 281,224 adults ≥21 (median age 59.8; 77.1% female), <21 samples showed more Bethesda V/VI cytology (14.5% vs 5.0%; p<0.0001) and a lower GSC-B rate (43.5% vs 68.8%; p<0.0001). In GSC-S samples, total variant detection was higher in <21 (45.3% vs 37.4%), with enriched BRAF p.V600E, TSHR, and DICER1 variants, while HRAS variants were more common in adults (all p<0.01). Gene fusions involving RET, NTRK3 and ALK were enriched in <21 (14.5% vs 5.5%; p<0.0001). TERT promoter mutations were absent in <21 yrs GSC-S and Bethesda V/VI samples (vs 4.2% and 9.3% in adults). GSC-S <21 showed cell-cycle pathway enrichment. RET/NTRK/ALK-positive <21 demonstrated enrichment of angiogenesis and EMT pathways, higher ERK/EMT/FMT scores, and lower BRS/TDS scores vs genotyped-matched adults. These molecular differences provide mechanistic insight into the more invasive phenotype in pediatric and young adult TN.
