JAMA：BRAF V600E突变与乳头状甲状腺癌显著相关

BRAF V600E是一个突出的PTC癌基因，相当多研究将其作为一个潜在的PTC预后因子。然而，这种突变与PTC死亡率的临床相关性尚未建立。日前，一项最新研究证实BRAF V600E基因突变的存在与甲状腺乳头状癌（PTC）患者死亡增加相关，但由于PTC总死亡率低，这种相关性不依赖于肿瘤特征，此信息用于预测PTC患者死亡风险的价值目前还不清楚。研究结论在线发表在2013年4月10日出版的JAMA杂志上。
美国约翰霍普金斯大学医学院Mingzhao Xing医学博士和他的同事进行了此项研究，旨在评估和定义BRAF V600E突变和PTC相关死亡率之间的关联。这项回顾性研究包括了1,849例（1,411名妇女和438名男子）患者，中位数年龄为46岁，整体中位随访时间为33个月，在1978年和2011年间在7个国家的13个医疗中心接受初步治疗。主要结局为PCT特异性死亡率。
结果发现，BRAF V600E阳性和突变阴性患者人群的总体死亡率分别为5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001)。对所有PTC患者的分析显示，BRAF V600E阳性和突变阴性患者组每1000人年死亡人数分别为12.87例(95% CI, 9.61-17.24) vs 2.52例(95% CI, 1.40-4.55)，校正诊断时年龄，性别以及医疗中心差异后的比值比(HR)为2.66 (95% CI, 1.30-5.43)。对于传统突变型BRAF V600E阳性和突变阴性患者组的分析显示每1000人年的死亡数分别为11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00)。这一模型包含了淋巴结转移，甲状腺外侵袭，以及远端转移等情形，此时对于所有PTC患者人群而言BRAF V600E突变与死亡率之间的联系不再显著(HR, 1.21; 95% CI, 0.53-2.76)。研究者在若干临床亚组分析中发现了更高的BRAF V600E相关性死亡，但当校正患者年龄，性别及医疗中心差异后，统计学意义丢失。举例说明如下，对于淋巴结转移患者，BRAF V600E阳性和突变阴性患者人群的每1000人年死亡数目为26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) (未校正HR, 4.43 [95% CI, 2.06-9.51]; 校正后HR, 1.46 [95% CI, 0.62-3.47])。对于远端转移患者，BRAF V600E阳性和突变阴性患者人群的每1000人年死亡数目分别为87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) (未校正HR, 2.63 [95% CI, 1.21-5.72]; 校正后HR, 0.84 [95% CI, 0.27-2.62])。
研究发现，BRAF V600E突变占总患病率的45.7％(845/1,849)。有56 例PTC死亡病例，占总死亡率的3.0％。在这些死亡中，45例（80.4％）呈阳性BRAF V600E。而当侵袭性肿瘤淋巴结转移，甲状腺外浸润和远处转移也纳入分析后，BRAF V600E与PTC死亡率的相关性已不再显著。总之，这个多中心研究证实BRAF V600E突变的存在与PTC患死亡率增加相关。
在这一回顾性多中心研究中，研究者由此得出结论，BRAF V600E突变的存在与PTC患者人群癌症相关性死亡率的增加显著性相关。因为PTC患者的总死亡率低，这种相关性不依赖于肿瘤特征，此信息用于预测PTC患者死亡风险的价值目前还不清楚。这些发现支持对PTC患者BRAF V600E突变的预后和治疗意义进行进一步的研究。
甲状腺乳头状癌是最常见的内分泌恶性肿瘤，约占全部甲状腺癌的85％到90％。PTC患者的5年生存率为95％至97％。”临床的一个主要挑战是，如何可靠地分辨哪些病人需要积极的治疗以降低死亡率，哪些病人不需要积极治疗。这是一个广泛争议的问题，特别是因为这种癌症总死亡率低。但随着PTC每年的高发病率，这个问题已经变得更具挑战性。
BRAFv600E基因突变是甲状腺乳头状癌中最常见的遗传学事件,是浸润性肿瘤临床表型和预后不佳的指标.BRAFV600E因突变检测对甲状腺恶性结节的术前鉴别诊断及指导甲状腺癌的手术切除范围、判断患者预后、指导术后后继治疗均有重要的指导意义。
与甲状腺癌相关的拓展阅读：

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• 2012中国甲状腺结节和分化型甲状腺癌指南
• Lancet Oncol：药物凡德他尼增加甲状腺癌病人无疾病恶化存活期
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Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer.
Importance 
BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established.
Objective 
To investigate the relationship between BRAF V600E mutation and PTC-related mortality.
Design, Setting, and Participants 
Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011.
Main Outcomes and Measures 
Patient deaths specifically caused by PTC.
Results 
Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E–positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E–positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E–positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E–associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E–positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E–positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]).
Conclusions and Relevance
In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.