Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer.
Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer.
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DOI：
10.1001/jama.2013.3190
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发表时间：
2013-04-10
影响因子：
120.7
通讯作者：
Sykorova, Vlasta
中科院分区：
文献类型：
--
作者：
Xing, Mingzhao;Alzahrani, Ali S.;Carson, Kathryn A.;Viola, David;Elisei, Rossella;Bendlova, Bela;Yip, Linwah;Mian, Caterina;Vianello, Federica;Tuttle, R. Michael;Robenshtok, Eyal;Fagin, James A.;Puxeddu, Efisio;Fugazzola, Laura;Czarniecka, Agnieszka;Jarzab, Barbara;O'Neill, Christine J.;Sywak, Mark S.;Lam, Alfred K.;Riesco-Eizaguirre, Garcilaso;Santisteban, Pilar;Nakayama, Hirotaka;Tufano, Ralph P.;Pai, Sara I.;Zeiger, Martha A.;Westra, William H.;Clark, Douglas P.;Clifton-Bligh, Roderick;Sidransky, David;Ladenson, Paul W.;Sykorova, Vlasta
BRAF V600E是甲状腺乳头状癌(PTC)中一个重要的癌基因，但其在PTC相关患者死亡率中的作用尚未确定。探讨BRAF V600E突变与PTC相关死亡率的关系。对1978年至2011年间在7个国家和地区的13个中心的1849名患者(1411名女性和438名男性)进行了回顾性研究，他们的中位年龄为46岁(四分位数范围，34-58岁)，总体中位随访时间为33个月(四分位数范围，13-67个月)。患者死亡的具体原因是PTC。总体而言，BRAF V600E阳性与突变阴性患者的死亡率分别为5.3%(45/845；95%可信区间，3.9%~7.1%)和1.1%(11/1004；95%可信区间，0.5%~2.0%)(P<；.001)。在所有PTC分析中，BRAF V600E阳性与突变阴性患者每1000人年的死亡率分别为12.87(95%CI，9.61~17.24)和2.52(95%CI，1.40~4.55)，调整了诊断、性别和医疗中心的年龄后，危险比(HR)为2.66(95%CI，1.30~5.43)。在传统PTC变异分析中，BRAF V600E阳性与突变阴性患者每1000人年死亡率分别为11.80(95%CI，8.39-16.60)和2.25(95%CI，1.01-5.00)，调整后的HR为3.53(95%CI，1.25-9.98)。当模型中还包括淋巴结转移、甲状腺外侵犯和远处转移时，BRAF V600E与所有PTC的死亡率之间的关联不再显著(HR，1.21；95%CI，0.53-2.76)。在几个临床病理亚类中也观察到了与BRAF V600E相关的较高的患者死亡率，但在调整患者的年龄、性别和医疗中心后失去了统计学意义。例如，在有淋巴结转移的患者中，BRAF V600E阳性和突变阴性患者的每1000人年死亡率分别为26.26(95%CI，19.18-35.94)和5.93(95%CI，2.96-11.86)(未调整HR，4.43[95%CI，2.06-9.51]；调整HR，1.46[95%CI，0.62-3.47])。在有远处转移的患者中，BRAF V600E阳性与突变阴性患者的每千人年死亡率分别为87.72(95%CI，62.68~122.77)和32.28(95%CI，16.14~64.55)(未调整的HR为2.63[95%CI，1.21~5.72]；调整后的HR为0.84[95%CI，0.27~2.62])。在这项多中心的回顾性研究中，BRAF V600E突变的存在与PTC患者癌症相关死亡率的增加显著相关。由于PTC的总死亡率很低，而且这种相关性并不独立于肿瘤特征，因此如何使用BRAF V600E来管理PTC患者的死亡风险尚不清楚。这些发现支持进一步研究BRAF V600E状态在PTC中的预后和治疗意义。
BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. To investigate the relationship between BRAF V600E mutation and PTC-related mortality. 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. Patient deaths specifically caused by PTC. 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]). 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.
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DOI：
10.1093/jnci/95.8.625
发表时间：
2003-04-16
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Cohen, J;Xing, MZ;Sidransky, D
通讯作者：
Sidransky, D
影响因子：
6.2
作者：
Kim, Tae Hyuk;Park, Young Joo;Park, Do Joon
通讯作者：
Park, Do Joon
影响因子：
6.8
作者：
Pelizzo, Maria Rosa;Boschin, Isabella Merante;Mian, Caterina
通讯作者：
Mian, Caterina
影响因子：
5.8
作者：
Puxeddu, E;Moretti, S;Santeusanio, F
通讯作者：
Santeusanio, F
影响因子：
8
作者：
Fukushima, T;Suzuki, S;Takenoshita, S
通讯作者：
Takenoshita, S