背景:激活BRAF基因改变是黑素细胞肿瘤发病机制的核心。一个小,由BRAF融合驱动的新出现的黑素细胞肿瘤子集具有不同的治疗意义,并且已被描述为具有Spitzoid形态模式.然而,这种形态模式并不涵盖所有情况,对功能性分子事件知之甚少。
方法:我们通过我们的分子档案进行了回顾性搜索,以鉴定BRAF融合的黑素细胞肿瘤。我们回顾了临床,组织病理学,和基因组特征。我们进一步探索了转录组和蛋白质水平的发现。
结果:组织病理学模式各不相同,许多案例没有独特的模式。我们鉴定了新颖多样的BRAF基因融合伴侣。低风险BRAF融合肿瘤和参考BRAFV600E肿瘤之间的差异转录组分析显示没有差异表达基因。然而,与BRAFV600E肿瘤相比,BRAF融合肿瘤的MAPK通路激活在统计学上显著更强的p-ERK免疫组织化学染色证实。基因特异性RNA分析显示两组之间相当的BRAF转录物水平。
结论:BRAF融合瘤的MAPK通路在数量上更强的激活,而不是定性不同的转录组,可能解释了与传统BRAFV600E肿瘤的形态学差异。BRAF融合可能通过失调的蛋白质功能而不是与融合伴侣的特征相关的RNA上调起作用。
BACKGROUND: Activating BRAF gene alterations are central to melanocytic tumor pathogenesis. A small, emerging subset of melanocytic tumors driven by BRAF fusions has distinct therapeutic implications and has been described to have Spitzoid morphology patterns. However, such morphological patterns do not encompass all cases, and little is known about the functional molecular events.
METHODS: We conducted a retrospective search through our molecular archives to identify melanocytic tumors with BRAF fusions. We reviewed clinical, histopathological, and genomic features. We further explored transcriptomic and protein-level findings.
RESULTS: Histopathologic patterns varied, with many cases without a distinctive pattern. We identified novel and diverse BRAF gene fusion partners. Differential transcriptomic analysis between low-risk BRAF fusion tumors and reference BRAF V600E tumors showed no differentially expressed genes. However, quantitatively stronger MAPK pathway activation of BRAF fusion tumors over BRAF V600E tumors was demonstrated by statistically significant stronger staining of p-ERK immunohistochemistry. Gene-specific RNA analysis shows comparable BRAF transcript levels between the two groups.
CONCLUSIONS: The quantitatively stronger activation of the MAPK pathway of BRAF fusion tumors, instead of qualitatively different transcriptomes, may account for the morphology difference from conventional BRAF V600E tumors. BRAF fusions likely act through dysregulated protein function rather than RNA upregulation related to the characteristics of the fusion partners.