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Association Between Somatic Mutation and Clinical Features in Korean Patients with Thyroid Cancer : 한국인 갑상선암의 체성돌연변이의 빈도와 임상상과의 연관성 연구

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의과대학 의학과
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서울대학교 대학원
Thyroid Cancer
학위논문 (박사)-- 서울대학교 대학원 : 의학과 분자유전체의학전공, 2015. 8. 박영주.
Introduction : Thyroid cancer incidence rates have increased steadily over the last 40 years, this it is the most common malignancy worldwide. Although main cause of increase is generally thought as the early diagnosis of thyroid cancer using ultrasonography, some environmental and genetic factors also have been suggested. In Korea, the reported incidence of BRAF mutation in papillary thyroid cancer (PTC) is around 70-80% showing the highest rate all over the world. On the other hand, the frequency of other genetic mutation such as RAS, RET/PTC or PAX8/PPARγ was considered to be relatively low. The purpose of this study was to elucidate the prevalence of somatic mutation in this BRAF-V600E-prevalent area and its clinical implication
Materials and Methods : We reviewed 606 BRAF-wild type PTC and 174 follicular thyroid cancer (FTC) cases who underwent total thyroidectomy at Seoul National University Hospital between 1997 and 2012. RAS and TERT point mutations of tumor DNA or RET, ALK and PPARγ rearrangements in the postoperative formalin-fixed paraffin-embedded samples were assessed by using direct sequencing, immunohistochemistry or fluorescence in situ hybridization (FISH).
Results : RAS point mutations were shown in 9.2% of BRAF-wild type PTCs, consisting of 18 N-RAS 61, 1 RAS 60, 2 K-RAS 12/13 and 1 H-RAS 61 mutations, and an estimated rate of RAS mutation in all PTCs was 2.4%. The frequency of RET rearrangement was 8.8% of BRAF-WT PTC, and its estimated frequency among all PTC was 2.6%. RAS mutation was significantly more common in follicular variant PTC than in conventional type (29.2% vs 2.8%, p<0.001). Among all type of PTC, the prevalence of conventional type was 80.1% and that of follicular variant type was only 14.8%. Mean tumor size is significantly larger (1.9 ± 1.5cm vs 1.2 ± 0.8cm, p=0.027), but LN metastases and are less common in RAS mutant PTC, compared with RAS-wild type PTC (4.5% vs 40.2%, p=0.001). ALK rearrangements were found in 4 cases of 218 BRAF-wild type PTCs (1.8%) by using immunohistochemistry and FISH analysis, and an estimated rate of ALK rearrangements in all PTC was 0.5%. TERT mutations were found in 18 of 433 PTC cases (4.2%). Tumor recurrence was 41 of 373 (11.0%) in TERT mutations-negative cases versus 6 of 18 (33.3%) in TERT mutation-positive cases (hazard ratio [HR] 3.38
95% CI 1.87 to 8.42
p = 0.005). Disease-free survival curves displayed a moderate decline with TERT mutation. In FTC, RAS mutation were found in 44 (23.4%) among 148 patients, but there were no significant difference between RAS-mutant and RAS-wild type FTC groups. Two PPARγ rearrangements (3.3%) were discovered in 61 FTC, but we found no PPARγ rearrangement in follicular variant PTC. TERT mutations were found in 7 of 120 FTC cases (5.8%). Tumor recurrence was 6 of 109 (5.5%) in TERT mutations-negative cases versus 2 of 7 (28.6%) in TERT mutation-positive cases (HR 7.22
95% CI 1.39 to 37.45
p = 0.019).
Conclusions : The prevalence of RAS mutation in Korea was relatively low, due primarily to low proportion of follicular variant in all PTCs. The percentage of RET rearrangements also showed low, suggesting different etiologic factors in Korea, compared with other countries. TERT promoter mutations were associated with aggressive clinicopathological outcomes in both PTC and FTC.
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