Esther N Klein Hesselink1, Carles Zafon2,3,4,5, Núria Villalmanzo6, Carmela Iglesias5,7, Bettien M van Hemel8, Mariëlle S Klein Hesselink1, Cristina Montero-Conde9, Raquel Buj5,6, Dídac Mauricio4,5,10, Miguel A Peinado5,6, Manel Puig-Domingo4,5,10,11, Garcilaso Riesco-Eizaguirre12,13, Jordi L Reverter5,10, Mercedes Robledo9,11, Thera P Links1, Mireia Jordà5,6. 1. Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 2. Diabetes and Metabolism Research Unit, Vall d'Hebron University Hospital, Barcelona, Spain. 3. Department of Endocrinology, Vall d'Hebron University Hospital, Autonomous University of Barcelona, Barcelona, Spain. 4. Biomedical Research Networking Center in Diabetes and Associated Metabolic Diseases, CIBERDEM, Institute of Health Carlos III, Madrid, Spain. 5. Consortium for the Study of Thyroid Cancer, CECaT, Barcelona, Spain. 6. Program for Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute, Badalona, Barcelona, Spain. 7. Department of Pathology, Vall D'Hebron University Hospital, Barcelona, Spain. 8. Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 9. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain. 10. Department of Endocrinology and Nutrition, Germans Trias i Pujol Research Institute and University Hospital, Badalona, Spain. 11. Biomedical Research Networking Center in Rare Diseases, CIBERER, Institute of Health Carlos III, Madrid, Spain. 12. Department of Endocrinology and Nutrition, Hospital Universitario de Móstoles, Madrid, Spain. 13. Biomedical Research Networking Center in Oncology, CIBERONC, Institute of Health Carlos III, Madrid, Spain.
Abstract
Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation.
Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation.
Authors: Zubair W Baloch; Sylvia L Asa; Justine A Barletta; Ronald A Ghossein; C Christofer Juhlin; Chan Kwon Jung; Virginia A LiVolsi; Mauro G Papotti; Manuel Sobrinho-Simões; Giovanni Tallini; Ozgur Mete Journal: Endocr Pathol Date: 2022-03-14 Impact factor: 3.943