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Gahee Park Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of
Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Tae Hyuk Kim Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Hae-Ock Lee Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Jung Ah Lim Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of
Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Jae-Kyung Won Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Hye Sook Min Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Kyu Eun Lee Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Do Joon Park Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Young Joo Park Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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Woong-Yang Park Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of
Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of
Samsung Genome Institute, Internal Medicine, Surgery, Biomedical Sciences, Department of Internal Medicine, Department of Molecular Cell Biology, Samsung Medical Center, 50 Irwondong, Gangnamgu, Seoul 135-710, Korea Departments of

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The anaplastic lymphoma kinase (ALK) gene is frequently rearranged in various types of cancer and is highly responsive to targeted therapeutics. We developed a system to detect rearrangement of ALK in a large group of Korean thyroid cancer patients. We screened 474 malignant or benign thyroid tumor cases to identify ALK fusions. Expression and translocation of the ALK gene were analyzed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and digital multiplexed gene expression (DMGE) analysis in formalin-fixed paraffin-embedded tissues. Four cases of rearrangement of ALK were detected by IHC, and these cases were validated with FISH on 189 samples. On the other hand, DMGE analysis using Nanostring detected three out of four IHC-positive cases. Two rearrangements of ALK were striatin (STRN)–ALK fusions, which were identified by 5′ RACE analysis. Rearrangements of ALK were found exclusively in v-raf murine sarcoma viral oncogene homolog B (BRAF) WT papillary carcinomas. Given the wide availability and accuracy of IHC for detecting ectopic expression of ALK in the thyroid, we suggest that IHC-based screening can be a practical method for identifying patients with ALK rearrangements in differentiated thyroid cancer.

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Tae Hyuk Kim Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Young-Eun Kim Green Cross Genome, Yongin, Korea

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Soomin Ahn Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Ji-Youn Kim Center for Clinical Medicine, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

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Chang-Seok Ki Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Young Lyun Oh Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Kyunga Kim Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jae Won Yun Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea

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Woong-Yang Park Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea

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Jun-Ho Choe Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jung-Han Kim Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jee Soo Kim Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Sun Wook Kim Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jae Hoon Chung Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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TERT promoter mutations are emerging prognostic biomarkers in multiple cancers and are found in highly aggressive thyroid cancer. Our aim is to investigate the prognostic value of these mutations for the outcome of thyroid cancer-related mortality in a large cohort of thyroid cancer patients. This was a retrospective study of 409 patients (393 with differentiated thyroid cancer) with a median age of 44 years (range 16–81 years) and median follow-up of 13 years (interquartile range 11–16 years). Analyses of associations between mutational status and various clinicopathological variables were performed. TERT promoter mutations were identified in 32 (9.8%) papillary, 11 (16.7%) follicular and seven (43.8%) poorly differentiated/anaplastic thyroid cancer patients. The presence of TERT promoter mutations was associated with factors such as increased age (P < 0.001), extrathyroidal invasion (P = 0.01), increased stage at diagnosis (P < 0.001) and dedifferentiated histological type (P = 0.001). A TERT promoter mutation was independently associated with poorer overall survival in patients with differentiated thyroid cancer (10-year survival rate, 66.2% vs 98.3% for wild type; adjusted HR, 7.18; 95% CI: 2.77–18.59) and in patients with papillary cancer (74.2% vs 99.3%; 14.20; 3.03–66.68). Concomitant TERT and BRAF mutations worsened the survival rate of patients with papillary cancer (82.6% vs 99.4% for exclusively BRAF mutation alone; 5.62; 1.85–17.09). In conclusion, the presence of TERT promoter mutations is independently associated with increased mortality in patients with differentiated thyroid cancer. The results suggest that inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

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