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甲状腺癌在内分泌系统的恶性肿瘤中最为常见,按组织学分类分为甲状腺乳头状癌(papillary thyroid carcinoma,PTC)、甲状腺滤泡癌(follicular thyroid carcinoma,FTC)、甲状腺未分化癌(anaplastic thyroid carcinoma,ATC)和甲状腺髓样癌(medullary thyroid carcinoma,MTC),其发病率分别为80%、15%、2%和3%,其中PTC的发病率最高[1]。PTC的发病率以超过6%的速度逐年增长,近30年来,我国甲状腺癌患者的发病率增长了近3倍[2]。我国癌症中心2017年2月的统计数据分析结果显示,甲状腺癌在我国大、中、小城市的发病率分别为28.9%、12.9%和7.8%[3]。随着超声造影联合弹性成像技术和超声引导下穿刺活检的普遍应用及其他诊断技术的发展,最大径≤1 cm的甲状腺微小乳头状癌也能被检出[4]。虽然大多数甲状腺癌患者的生存率较高,但有15%~20%的患者会发生肿瘤复发或远处转移,10年生存率下降40%~85% [5]。
目前,甲状腺癌中最为常见且研究比较深入的分子缺陷是BRAF基因突变,其在甲状腺癌中的发生率为15%~75%[1],在PTC患者中BRAFV600E突变率为30%~69%[6],BRAFV600E与PTC的分类、分期、甲状腺外侵袭(extrathyroidal extension, ETE)及病灶摄碘与否等存在一定的相关性,其主要作用机制有两方面。(1)致瘤机制:BRAF基因15号外显子激活V600E突变,随之级联激活RAS-RAF-MEK-ERK信号通路,促进细胞的分裂、增殖和上皮间充质转化(EMT)等,从而导致肿瘤的发生[7]。(2)抑制碘代谢相关基因机制:BRAFV600E突变通过转化生长因子(transforming growth factor,TGF)beta-SMAD3即 TGFβ-SMAD3和MEK-ERK信号通路,减少双链复合蛋白8(PAX-8)与钠/碘同向转运体(sodium/iodine symporter,NIS)上游增强子的结合,导致NIS表达水平降低及其在细胞膜表面定位的数量减少[8]。
在PTC患者中,针对BRAFV600E突变与PTC患者临床不良预后的相关性问题,美国甲状腺癌协会指出BRAF基因突变的存在可以作为临床预后不佳的危险因素之一[9]。但是BRAFV600E突变能否作为PTC患者高风险临床病理特征(淋巴结转移、ETE、高TNM分期等)及预后不良的独立危险因素,这在医学界一直存在着争议,我们现将 BRAFV600E突变与PTC临床病理特点及预后不良之间的关系综述如下。
BRAFV600E突变与甲状腺乳头状癌临床病理特征及不良预后的相关性
Relationship between BRAFV600E mutation and pathological features and clinical poor prognosis of PTC
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摘要: 甲状腺癌在内分泌系统的恶性肿瘤中最为常见,按组织学分类分为甲状腺滤泡癌、甲状腺乳头状癌(PTC)、甲状腺髓样癌及甲状腺未分化癌,其中PTC最为常见。目前认为PTC的最佳治疗方案是手术切除、131I治疗及甲状腺激素替代抑制治疗,但小部分患者会发生肿瘤复发或转移,10年生存率显著下降40%~85%。不同的临床病理学特征,如淋巴结转移、甲状腺外侵袭和TNM分期等将出现不同的预后(复发、转移和死亡等)情况。因此,上述临床病理学特征也被用于预测PTC患者的预后情况,能尽早辨识此类风险因素,将争取更多时间进行相应的干预治疗并改善预后。笔者就BRAFV600E突变与PTC患者的临床病理学特征及预后情况的关系展开综述。
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关键词:
- 甲状腺癌,乳头状 /
- BRAFV600E基因 /
- 点突变 /
- 预后 /
- 碘放射性同位素
Abstract: Thyroid cancer is the most common malignant tumor in the endocrine system, which can be divided into follicular thyroid cancer, papillary thyroid cancer (PTC), medullary thyroid carcinoma and anaplastic thyroid carcinoma. Among them, PTC is the most common pathological subtype. At present, surgical resection, 131I therapy and thyroid hormone replacement inhibition therapy are considered as the best treatments for PTC, but a small part of patients will undergo tumor recurrence or metastasis and their 10 years survival rate will be significantly reduced by 40% ~ 85%. Different clinical pathological features, such as lymph node metastasis, extrathyroid invasion, TNM stage will cause different prognosises (recurrence, metastasis, death, etc.). Therefore, the clinicopathological features above are also used to predict the prognosis of patients with PTC, and identifying such risk factors as soon as possible will buy more time for appropriate intervention and treatment to improve the prognosis. This paper reviews the relationship between BRAFV600E mutation and the clinicopathological features above and clinical poor prognosis of patients with PTC.-
Key words:
- Thyroid cancer, papillary /
- BRAFV600E gene /
- Point mutation /
- Prognosis /
- Iodine radioisotopes
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