表浅扩散黑素瘤（SSMs）是最常见的黑色素瘤类型，导致大部分皮肤癌死亡。超过50%的案例携带BRAF基因突变，激活丝裂原活化蛋白激酶（MAPK）癌症信号通路。BRAFV600E是最常见的BRAF突变，并且代表了指导治疗选择的重要生物标志物。然而，BRAFV600E基因表达和肿瘤内蛋白分布与临床病理和患者预后之间的关系尚未完全描述。此外，黑色素瘤中MAPK癌症信号通路的激活是否由于BRAFV600E的生化活性增加，mRNA水平增加，还是两者都需要进一步研究。在此，我们通过检查原始治疗无经验的黑色素瘤中BRAFV600E的表达模式，并将其与临床病理因素和患者预后相关联，解决了这些问题。 在166个SSM病例中，我们进行了免疫组化染色以调查BRAFV600E的蛋白表达，并使用NanoString nCounter系统测量了BRAF mRNA水平。97个（49%）黑色素瘤对BRAFV600E呈阳性染色，观察到近100%的肿瘤内均一性。阳性BRAFV600E表达与非复发性疾病显著相关，并在单变量和多变量分析中被发现是更好预后的独立预测因子。此外，肿瘤浸润淋巴细胞的存在，哨兵淋巴结活检阴性和Breslow厚度低都是更好预后的独立预测因子。我们观察到，BRAFV600E阴性和BRAFV600E阳性黑色素瘤之间的BRAF mRNA水平没有差异。在更大的公开队列中进行验证，确认BRAFV600E mRNA和蛋白水平之间只有很弱的相关性（Spearman 0.4），在BRAFV600E突变和非突变患者之间没有mRNA的差异。 我们的发现表明，BRAFV600E在整个肿瘤中均匀存在，并与原发性黑色素瘤中的非复发性疾病和更好的生存率相关。我们还表明，BRAFV600E突变不会导致更高的转录水平，这表明BRAFV600E突变患者的MAPK信号通路的激活可归因于突变引起的生化活性增加。©2023 S. Karger AG，巴塞尔。

Superficial spreading melanomas (SSMs) are the most common type of melanoma and cause the majority of skin cancer deaths. More than 50% of cases harbor a mutation in the BRAF gene that activates the mitogen-activated protein kinase (MAPK) cancer signaling pathway. BRAFV600E is the most common BRAF mutation, and it represents an important biomarker that guides treatment selection. However, the relationship between the BRAFV600E gene expression and intratumoral protein distribution, on one side, and clinicopathological factors and patient outcomes, on the other, is not fully described. Additionally, whether MAPK cancer signaling activation in melanoma is due to increased biochemical activity of BRAFV600E, increased mRNA levels, or both requires further investigation. Here, we addressed these questions by examining expression patterns of BRAFV600E in primary treatment-naive melanomas and correlating them to clinicopathological factors and patient outcomes.In 166 SSM cases, we performed immunohistochemical staining to investigate the protein expression of BRAFV600E, and we measured BRAF mRNA levels using NanoString nCounter system.Ninety-seven (49%) melanomas stained positive for BRAFV600E, with nearly 100% intratumoral homogeneity observed. Positive BRAFV600E expression was significantly associated with nonrecurrent disease and was found to be an independent predictor of better prognosis in univariate and multivariable analyses. Furthermore, presence of tumor-infiltrating lymphocytes, sentinel lymph node biopsy negativity, and low Breslow thickness were all independent predictors of better prognosis. We observed no difference in the BRAF mRNA levels in BRAFV600E-negative and BRAFV600E-positive melanomas, respectively. Validation in a larger publicly available cohort confirmed that there is only a weak correlation (Spearman 0.4) between BRAFV600E mRNA and protein levels and no differences in mRNA between BRAFV600E mutated and non-mutated patients.Our findings indicated that BRAFV600E is homogeneously present throughout the whole tumor and is associated with nonrecurrent disease and better survival in primary melanoma. We also showed that BRAFV600E mutation does not result in higher transcriptional levels, suggesting that activation of the MAPK signaling pathway in BRAFV600E mutated patients can be attributed to the increased biochemical activity caused by the mutation.© 2023 S. Karger AG, Basel.