A B-Raf V600E gene signature for melanoma predicts prognosis and reveals sensitivity to targeted therapies.
A B-Raf V600E gene signature for melanoma predicts prognosis and reveals sensitivity to targeted therapies.
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DOI：
10.1002/cam4.4491
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发表时间：
2022-03
期刊：
影响因子：
4
通讯作者：
Cheng C
中科院分区：
文献类型：
--
作者：
Yao K;Zhou E;Cheng C
B‐Raf V600 E突变约占所有皮肤黑色素瘤病例的一半，并且具有该突变的患者对BRAF抑制剂敏感。然而，MAPK/ERK通路中其他基因的畸变可能级联产生与B‐Raf V600 E突变相似的效应，使这些患者对BRAF抑制剂敏感。我们认为，基于B-Raf通路活性定义特征可能比突变状态等二元指标更能为预后和药物敏感性预测提供信息。在这项研究中，我们使用来自TCGA的RNA-seq数据定义了B-Raf特征评分。较高的评分不仅可以预测B-Raf突变状态，还可以预测其他类似激活MAPK/ERK通路的畸变，如B-Raf扩增、RAS突变和EGFR扩增。我们发现，与测量B-Raf畸变的其他指标（如突变状态、基因表达和蛋白质表达）相比，通过中位B-Raf评分进行二分的患者分层更显著。我们还证明，高B-Raf评分预测对B-Raf抑制剂SB 590885和PLX 4720的敏感性更高，正如预期的那样，但也与靶向其他相关致癌途径的药物的敏感性相关。BRAF签名可以更好地帮助指导黑色素瘤的靶向治疗，并且这样的框架可以应用于其他癌症和突变，以提供比单独的突变状态更多的信息。我们捕获BRAF V600 E突变途径活性的BRAF评分与对BRAF抑制剂以及其他靶向治疗的敏感性相关。该评分还能够预测预后和对免疫疗法的反应。
B‐Raf V600E mutations account for about half of all skin cutaneous melanoma cases, and patients with this mutation are sensitive to BRAF inhibitors. However, aberrations in other genes in the MAPK/ERK pathway may cascade a similar effect as B‐Raf V600E mutations, rendering those patients sensitive to BRAF inhibitors. We rationalized that defining a signature based on B‐Raf pathway activity may be more informative for prognosis and drug sensitivity prediction than a binary indicator such as mutation status. In this study, we defined a B‐Raf signature score using RNA‐seq data from TCGA. A higher score is shown to not only predict B‐Raf mutation status, but also predict other aberrations that could similarly activate the MAPK/ERK pathway, such as B‐Raf amplification, RAS mutation, and EGFR amplification. We showed that patients dichotomized by the median B‐Raf score is more significantly stratified than by other metrics of measuring B‐Raf aberration, such as mutation status, gene expression, and protein expression. We also demonstrated that high B‐Raf score predicts higher sensitivity to B‐Raf inhibitors SB590885 and PLX4720, as expected, but also correlated with sensitivity to drugs targeting other relevant oncogenic pathways. The BRAF signature may better help guide targeted therapy for melanoma, and such a framework can be applied to other cancers and mutations to provide more information than mutation status alone. Our BRAF score that captures BRAF V600E mutation pathway activity correlates with sensitivity to BRAF inhibitors, as well as other targeted therapies. The score is also able to predict prognosis and response to immunotherapy.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
1.6
作者：
Hannan EJ;O'Leary DP;MacNally SP;Kay EW;Farrell MA;Morris PG;Power CP;Hill ADK
通讯作者：
Hill ADK
DOI：
10.1038/modpathol.2017.104
发表时间：
2018-01
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
Cheng L;Lopez-Beltran A;Massari F;MacLennan GT;Montironi R
通讯作者：
Montironi R
影响因子：
6.6
作者：
Kannengiesser, Caroline;Spatz, Alain;Bressac-de Paillerets, Brigitte
通讯作者：
Bressac-de Paillerets, Brigitte
DOI：
10.1158/1078-0432.ccr-14-3214
发表时间：
2015-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cox AD;Der CJ;Philips MR
通讯作者：
Philips MR