Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care.
Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care.
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DOI：
10.1186/s12885-017-3529-5
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发表时间：
2017-08-10
期刊：
影响因子：
3.8
通讯作者：
Berking C
中科院分区：
文献类型：
--
作者：
Heppt MV;Siepmann T;Engel J;Schubert-Fritschle G;Eckel R;Mirlach L;Kirchner T;Jung A;Gesierich A;Ruzicka T;Flaig MJ;Berking C
癌基因 BRAF 和 NRAS 的热点突变是皮肤黑色素瘤中最常见的遗传改变。 BRAF 和 MEK 的特异性抑制剂在大型 III 期试验中显示出显着的生存益处。然而，临床试验之外的 BRAF 和 NRAS 突变的预后意义仍不清楚。通过焦磷酸测序和桑格测序确定了 217 名患者黑色素瘤样本中 BRAF（外显子 15）和 NRAS（外显子 2 和 3）的突变状态。基因型与原发肿瘤的临床结果和病理特征相关。用累积发病率函数计算疾病进展时间。使用 Kaplan-Meier 估计和 Cox 比例风险回归分析进行生存分析。使用 Ederer-II 方法计算相对生存率。允许使用 BRAF 和 MEK 抑制剂以及免疫检查点阻断 (ICB) 进行治疗。分别在 40.1% 和 24.4% 的病例中发现 BRAF 和 NRAS 突变。另外 2.3% 的人还检测到了这两个基因的同时突变。其余 33.2% 为所研究外显子 (WT) 的野生型。 BRAF 突变与首次诊断时的年轻年龄 (p<0.001) 和原发罪魁祸首的躯干定位 (p=0.002) 显着相关。结节亚型在 NRAS 队列中最常见。此外，NRAS 突变黑色素瘤患者的淋巴结复发 (p = 0.013) 和转移性疾病 (p = 0.021) 的发生率更高。 NRAS 突变黑色素瘤的局部区域淋巴结复发时间最短 (p = 0.002)。多变量分析显示，NRAS 突变的存在是疾病进展的独立危险因素（HR 2.01；95% CI 1.02 – 3.98）。 BRAF 突变黑色素瘤患者表现出更好的总体生存率和相对生存率。在多变量分析中，基因型并不是一致的危险因素。相反，前哨淋巴结状态阳性（HR 2.65；95% CI 1.15 – 6.10）和 IV 期疾病 ICB 治疗（HR 0.17；95% CI 0.06–0.48）是显着的多变量危险因素。 NRAS 突变肿瘤往往表现得更具攻击性，尤其是在这种高风险黑色素瘤人群的疾病早期阶段。在现实世界中，免疫检查点阻断治疗可提高 IV 期疾病的生存率。本文的在线版本 (doi:10.1186/s12885-017-3529-5) 包含补充材料，可供授权用户使用。
Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear. The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed. Mutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p < 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 – 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 – 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06–0.48) were significant multivariate risk factors. NRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting. The online version of this article (doi:10.1186/s12885-017-3529-5) contains supplementary material, which is available to authorized users.
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DOI：
10.1158/1078-0432.ccr-10-2276
发表时间：
2011-01-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ellerhorst JA;Greene VR;Ekmekcioglu S;Warneke CL;Johnson MM;Cooke CP;Wang LE;Prieto VG;Gershenwald JE;Wei Q;Grimm EA
通讯作者：
Grimm EA
影响因子：
2.2
作者：
Edlundh-Rose, Esther;Egyhazi, Suzanne;Lundeberg, Joakim
通讯作者：
Lundeberg, Joakim
影响因子：
10.3
作者：
Schlaak, M.;Bajah, A.;Kurschat, P.
通讯作者：
Kurschat, P.
影响因子：
6.5
作者：
Joosse, Arjen;de Vries, Esther;Engel, Jutta
通讯作者：
Engel, Jutta
影响因子：
1.9
作者：
Sasieni, Peter;Brentnall, Adam R.
通讯作者：
Brentnall, Adam R.