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Gene expression signature associated with BRAF mutations in human primary cutaneous melanomas

机译:与人类原发性皮肤黑色素瘤的BRAF突变相关的基因表达特征

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摘要

With the aim to correlate BRAF mutation status with gene expression in human primary cutaneous melanomas, and thus to get more insight on the consequences of BRAF mutation on cell biology, we analyzed all expression data obtained in melanomas from which DNA was extracted from the same tissue slides that were used for the expression study.A cohort of 69 frozen primary melanoma whose oligonucleotide micro‐array expression data were available, were genotyped for BRAF and NRAS genes. The expression data from these melanomas were re‐analyzed according to BRAF mutational status.A set of 250 probes representing 209 genes that were significantly (raw P≤0.001) associated with BRAF mutation status was identified and 17 of these were previously shown to be implicated in cutaneous melanoma progression or pigmentation pathway‐associated genes driven by the microphthalmia transcription factor (MITF). The list of 34 top probes contained no more than 1% of false discoveries with a probability of 0.95. Among the genes that differentiated most strongly between BRAF mutated and non‐mutated melanomas, there were those involved in melanoma immune response such as MAGE‐D2, CD63, and HSP70.These findings support the immunogenicity of BRAFV600E, eliciting patients T‐cell responses in various in vitro assays. The genes whose expression is associated with BRAF mutations are not simply restricted to the MAPK/ERK signaling but also converge to enhanced immune responsiveness, cell motility and melanosomes processing involved in the adaptative UV response.
机译:为了使BRAF突变状态与人类原发性皮肤黑色素瘤中的基因表达相关联,从而更深入地了解BRAF突变对细胞生物学的影响,我们分析了在黑色素瘤中获得的所有表达数据,从相同组织中提取DNA对一组可获得寡核苷酸微阵列表达数据的69例冷冻原发性黑素瘤进行了BRAF和NRAS基因分型。根据BRAF突变状态重新分析了这些黑色素瘤的表达数据。共鉴定了250个代表209个与BRAF突变状态显着相关(原始P≤0.001)的基因的探针,其中17个以前被证明有牵连由小眼症转录因子(MITF)驱动的皮肤黑色素瘤进展或色素沉着途径相关基因34个顶级探针的列表包含不超过1%的错误发现,概率为0.95。在BRAF突变的和未突变的黑色素瘤之间差异最大的基因中,有一些参与了黑色素瘤免疫应答的基因,例如MAGE-D2,CD63和HSP70,这些发现支持BRAFV600E的免疫原性,引发了患者的T细胞应答。各种体外测定。其表达与BRAF突变相关的基因不仅限于MAPK / ERK信号传导,而且还可以聚合为适应性UV反应所涉及的增强的免疫反应性,细胞运动性和黑素体加工。

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