ETA2024 Poster Presentations Basic thyroid cancer research-1 (10 abstracts)
Exploring the genetic links between voltage-gated potassium channels and familial non-medullary thyroid carcinoma: a family study
Elisabete Teixeira 1 , Lia Rodrigues 2 , Marta Cardoso 3 , Cláudia Fernandes 4 , Arnaud da Cruz Paula 1 , Raquel Lima 3 , Marta Ferreira 5 , Teresa Martins 6 , Andreia Fernandes 6 , Fernando Rodrigues 6 , Hugo Prazeres 7 & Paula Soares 8
1I3s - Instituto de Investigação e Inovação Em Saúde; Fmup - Faculdade de Medicina Da Universidade Do Porto, Ipatimup - Instituto de Patologia e Imunologia Molecular Da Universidade Do Porto, Porto, Portugal; 2I3s - Instituto de Investigação e Inovação Em Saúde; Fmup - Faculdade de Medicina Da Universidade Do Porto; Área Técnico-Científica de Ciências Morfológicas, Escola Superior de Saúde Do Instituto Politécnico Do Porto, Ipatimup - Instituto de Patologia e Imunologia Molecular Da Universidade Do Porto, Porto, Portugal; 3I3s - Instituto de Investigação e Inovação Em Saúde, Ipatimup, Porto, Portugal; 4I3s - Instituto de Investigação e Inovação Em Saúde; Fcup - Faculdade de Ciências Da Universidade Do Porto; Icbas - Instituto de Ciências Biomédicas Abel Salazar Da Universidade Do Porto, Ipatimup - Instituto de Patologia e Imunologia Molecular Da Universidade Do Porto, Porto, Portugal; 5Instituto de Investigação e Inovação Em Saúde Da Universidade Do Porto, I3s - Instituto de Investigação e Inovação Em Saúde Da Universidade Do Porto, Expression Regulation in Cancer Research Group, Porto, Portugal; 6Instituto Português De Oncologia De Coimbra Francisco Gentil, Endocrinology, Coimbra, Portugal; 7I3s - Instituto de Investigação e Inovação Em Saúde, Ipatimup - Instituto de Patologia e Imunologia Molecular Da Universidade Do Porto, Porto, Portugal; 8Medical Faculty University of Porto, Ipatimup, Cancer Signaling and Metabolism Group, Porto, Portugal
Introduction: Our team identified a family where 5 elements developed thyroid cancer between the ages of 26 and 38. Since no syndromic form of the disease was found, the diagnosis was of familial non-medullary thyroid carcinoma (FNMTC). Our team employed Whole-Exome Sequencing (WES) and identified a new potentially pathogenic germline mutation in the KCNB2 gene [ p.(Gly106Arg)]. KCNB2 encodes a voltage-gated potassium channel (vgKCN), and the detected missense mutation is localized in the tetramerization domain of the protein, possibly affecting its assembly and K+ efflux. Since K+ efflux by the cell is a necessary condition for cellular homeostasis, channel disruption can impact the function of other ion channels nearby. Mice studies showed that KCNE2 disruption indirectly impairs sodium-iodide symporter (NIS) function, and therefore iodide uptake by the cell, resulting in hypothyroidism or follicular nodular disease.
Hypothesis: By indirect effect on NIS function vgKCN mutations may increase predisposition to thyroid cancer and interfere with radioiodine (RAI) therapy response.
Methodology: We conducted in silico studies using two different NGS databases, TCGA and one in-house oncocytic tumors database (513 and 18 patients, respectively). Alterations in 59 genes were searched for copy-number variation, point mutations and other genetic alterations. in vitro assays using the FRTL-5 cell line are being performed. FRTL-5 cells were transfected with overexpression vectors containing either KCNB2 wild-type or KCNB2 mutated sequences, and the empty vector (EV) as a negative control. Expression of thyroid markers (e.g. NIS, TSH receptor, Thyroglobulin and TPO) was evaluated by qPCR and cell viability by PrestoBlue assay. Protein expression of thyroid markers will be assessed by Western blot. Cell cycle and apoptosis through flow cytometry, cell morphology by phalloidin assay, and cell colony formation by crystal violet. Transformed cells will further be treated with Guangxitoxin-1E, a potent KCNB1 / KCNB2 inhibitor.
Results: Our in silico results show that vgKCN mutations are rare events in thyroid cancer [19/488 (4%) in TCGA; 3/18 (17%) in our in-house database]. BRAF and NRAS alterations are frequent events in vgKCN altered tumors (58% and 16%, respectively). No KCNB2 pathogenic mutations were observed. vgKCN mutations were not correlated with patient prognosis. Our in vitro preliminary results show that KCNB2 mutated cells present higher expression of the channel than KCNB2 wild-type cells. No differences in cell viability were found between KCNB2 wild-type and mutated cells.
Conclusions: If confirmed, vgKCN mutations may identify patients with altered RAI response, serving as thyroid cancer markers and potential pharmacological targets.
Volume 101
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Endocrine Abstracts
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