Clinical correlates of NRAS and BRAF mutations in primary human melanoma.
Clinical correlates of NRAS and BRAF mutations in primary human melanoma.
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DOI：
10.1158/1078-0432.ccr-10-2276
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发表时间：
2011-01-15
期刊：
影响因子：
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通讯作者：
Grimm EA
中科院分区：
文献类型：
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作者：
Ellerhorst JA;Greene VR;Ekmekcioglu S;Warneke CL;Johnson MM;Cooke CP;Wang LE;Prieto VG;Gershenwald JE;Wei Q;Grimm EA
NRAS和BRAF突变在皮肤黑色素瘤中很常见，尽管很少在同一肿瘤中同时检测到。尽管体外数据表明其致癌作用增强，但这些突变的独特临床相关性尚未得到描述。本研究旨在验证以下假设：在NRAS或BRAF中存在突变的原发性人类皮肤黑色素瘤比在这两个位点均为野生型的肿瘤表现出更具侵袭性的临床表型。
对223例原发性黑色素瘤进行了显微切割，随后确定了NRAS和BRAF的突变状态。基因型结果与已知影响肿瘤行为的特征相关联，包括年龄、性别、Breslow厚度、Clark分级、有丝分裂率、溃疡的存在以及美国癌症联合委员会（AJCC）分期。
不同基因型之间的Breslow厚度和Clark分级存在显著差异，NRAS突变体显示出最深的厚度，野生型肿瘤的厚度最浅。不同基因型之间的溃疡情况也存在显著差异，BRAF突变体的溃疡率最高。此外，NRAS突变的肿瘤更有可能位于四肢。与野生型肿瘤患者相比，肿瘤携带任一突变的患者在诊断时呈现出更晚期的AJCC分期，特别是更有可能患有III期疾病。三组之间的总体生存率没有差异。
无论是综合考虑还是单独考虑，携带NRAS和BRAF突变的黑色素瘤都存在独特的临床表型，并且与已知可预测肿瘤侵袭性行为的特征相关。这些突变的影响在疾病进展的早期阶段最为明显。
NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci. Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior, including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and AJCC staging. Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. Additionally, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared to patients with wild type tumors, and specifically, were more likely to have Stage III disease at diagnosis. Overall survival did not differ among the three groups. Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression.