Chan Kwon Jung1,2, Seung-Hyun Jung3,4, Sora Jeon1,2, Young Mun Jeong1,2,5, Yourha Kim1,2, Sohee Lee2,6, Ja-Seong Bae2,6, Yeun-Jun Chung4,7,8. 1. Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 2. Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 3. Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 4. Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 5. Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 6. Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 7. IRCGP, Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. 8. Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Abstract
Background: Although most differentiated thyroid carcinomas (DTCs) have indolent behavior, DTCs with distant metastasis have a poor prognosis. However, there are no validated markers that predict the risk of distant metastasis and the prognosis of DTC. We aimed to develop a genetic classifier for predicting the outcomes of DTC patients with distant metastases. Methods: Targeted deep sequencing of 157 cancer-related genes was performed for 61 DTCs with distant metastases. A candidate mutation was validated with independent thyroid cancer samples using digital polymerase chain reaction. Results: The most frequently mutated gene in the 61 DTCs was BRAF (n = 31, 51%), followed by TERT promoter (n = 28, 46%), NRAS (n = 13, 11%), PLEKHS1 promoter (n = 6, 10%), and STK11 (n = 6, 10%) mutations. PLEKHS1 promoter mutations were more common in the radioactive iodine (RAI)-refractory cases (p = 0.003). Losses of 9q and 11q were associated with RAI-refractory disease (p = 0.002) and cancer-specific mortality (p = 0.028), respectively. In multivariate analysis, bone metastasis (adjusted odds ratio [aOR] = 15.17, 95% confidence interval [CI 3.38-68.06], p < 0.001) and at least one mutation in the TERT promoter, the PLEKHS1 promoter, or TP53 (aOR = 7.64 [CI 1.78-32.76], p = 0.006) remained significant factors associated with RAI-refractoriness. In independently collected papillary thyroid carcinomas without initial distant metastasis (n = 75), a PLEKHS1 promoter mutation was only found in one case that developed distant metastasis during the follow-up period. We developed a genetic classifier consisting of BRAF, RAS, the TERT promoter, the PLEKHS1 promoter, and TP53 for categorizing the prognosis of patients with DTC with distant metastasis. In the poor-prognosis group, 61% of the patients were RAI-refractory and death occurred in 21% during the follow-up. In the intermediate-prognosis group, 29% were RAI-refractory, but no death occurred. In the good-prognosis group, all patients were RAI-responsive and no death occurred. Conclusions: Mutations in the PLEKHS1 promoter are a novel genetic marker of aggressive DTC. Our genetic classifier can be useful for predicting RAI-refractory disease and poor prognosis in DTC patients with distant metastases.
Background: Although most differentiated thyroid carcinomas (DTCs) have indolent behavior, DTCs with distant metastasis have a poor prognosis. However, there are no validated markers that predict the risk of distant metastasis and the prognosis of DTC. We aimed to develop a genetic classifier for predicting the outcomes of DTC patients with distant metastases. Methods: Targeted deep sequencing of 157 cancer-related genes was performed for 61 DTCs with distant metastases. A candidate mutation was validated with independent thyroid cancer samples using digital polymerase chain reaction. Results: The most frequently mutated gene in the 61 DTCs was BRAF (n = 31, 51%), followed by TERT promoter (n = 28, 46%), NRAS (n = 13, 11%), PLEKHS1 promoter (n = 6, 10%), and STK11 (n = 6, 10%) mutations. PLEKHS1 promoter mutations were more common in the radioactive iodine (RAI)-refractory cases (p = 0.003). Losses of 9q and 11q were associated with RAI-refractory disease (p = 0.002) and cancer-specific mortality (p = 0.028), respectively. In multivariate analysis, bone metastasis (adjusted odds ratio [aOR] = 15.17, 95% confidence interval [CI 3.38-68.06], p < 0.001) and at least one mutation in the TERT promoter, the PLEKHS1 promoter, or TP53 (aOR = 7.64 [CI 1.78-32.76], p = 0.006) remained significant factors associated with RAI-refractoriness. In independently collected papillary thyroid carcinomas without initial distant metastasis (n = 75), a PLEKHS1 promoter mutation was only found in one case that developed distant metastasis during the follow-up period. We developed a genetic classifier consisting of BRAF, RAS, the TERT promoter, the PLEKHS1 promoter, and TP53 for categorizing the prognosis of patients with DTC with distant metastasis. In the poor-prognosis group, 61% of the patients were RAI-refractory and death occurred in 21% during the follow-up. In the intermediate-prognosis group, 29% were RAI-refractory, but no death occurred. In the good-prognosis group, all patients were RAI-responsive and no death occurred. Conclusions: Mutations in the PLEKHS1 promoter are a novel genetic marker of aggressive DTC. Our genetic classifier can be useful for predicting RAI-refractory disease and poor prognosis in DTC patients with distant metastases.
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
Authors: Linwah Yip; William E Gooding; Alyaksandr Nikitski; Abigail I Wald; Sally E Carty; Esra Karslioglu-French; Raja R Seethala; Dan P Zandberg; Robert L Ferris; Marina N Nikiforova; Yuri E Nikiforov Journal: Cancer Date: 2021-02-04 Impact factor: 6.860
Authors: Mimi I Hu; Steven G Waguespack; Chrysoula Dosiou; Paul W Ladenson; Masha J Livhits; Lori J Wirth; Peter M Sadow; Jeffrey F Krane; Brendan C Stack; Mark E Zafereo; Syed Z Ali; Steven P Weitzman; Yangyang Hao; Joshua E Babiarz; Giulia C Kennedy; Richard T Kloos Journal: J Clin Endocrinol Metab Date: 2021-07-13 Impact factor: 5.958