Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.
Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations.
复制标题
复发的神经母细胞瘤显示出频繁的RAS-MAPK途径突变。
DOI：
10.1038/ng.3333
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发表时间：
2015-08
期刊：
影响因子：
30.8
通讯作者：
Maris JM
中科院分区：
文献类型：
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作者：
Eleveld TF;Oldridge DA;Bernard V;Koster J;Colmet Daage L;Diskin SJ;Schild L;Bentahar NB;Bellini A;Chicard M;Lapouble E;Combaret V;Legoix-Né P;Michon J;Pugh TJ;Hart LS;Rader J;Attiyeh EF;Wei JS;Zhang S;Naranjo A;Gastier-Foster JM;Hogarty MD;Asgharzadeh S;Smith MA;Guidry Auvil JM;Watkins TB;Zwijnenburg DA;Ebus ME;van Sluis P;Hakkert A;van Wezel E;van der Schoot CE;Westerhout EM;Schulte JH;Tytgat GA;Dolman ME;Janoueix-Lerosey I;Gerhard DS;Caron HN;Delattre O;Khan J;Versteeg R;Schleiermacher G;Molenaar JJ;Maris JM
大多数神经母细胞瘤患者的肿瘤最初对化疗有反应，但很大一部分患者会经历耐药性复发。这种侵袭性表型的分子基础尚不清楚。对23对诊断性和复发性神经母细胞瘤的全基因组测序显示，诊断性肿瘤的克隆进化具有复发样本特有的29个体细胞突变的中位数。23例复发肿瘤中的18例（78%）显示出预测激活RAS-MAPK信号通路的突变。仅在复发肿瘤中检测到7个事件，而其他事件显示克隆富集。在神经母细胞瘤细胞系中，我们还检测到RAS-MAPK通路中的高频率激活突变（11/18，61%），这些病变预测了体外和体内对MEK抑制的敏感性。我们的研究结果为复发性神经母细胞瘤的遗传特征提供了理论基础，并表明RAS-MAPK通路突变可能作为难治性疾病新治疗方法的生物标志物。
The majority of neuroblastoma patients have tumors that initially respond to chemotherapy, but a large proportion of patients will experience therapy-resistant relapses. The molecular basis of this aggressive phenotype is unknown. Whole genome sequencing of 23 paired diagnostic and relapsed neuroblastomas showed clonal evolution from the diagnostic tumor with a median of 29 somatic mutations unique to the relapse sample. Eighteen of the 23 relapse tumors (78%) showed mutations predicted to activate the RAS-MAPK signaling pathway. Seven events were detected only in the relapse tumor while the others showed clonal enrichment. In neuroblastoma cell lines we also detected a high frequency of activating mutations in the RAS-MAPK pathway (11/18, 61%) and these lesions predicted for sensitivity to MEK inhibition in vitro and in vivo. Our findings provide the rationale for genetic characterization of relapse neuroblastoma and show that RAS-MAPK pathway mutations may function as a biomarker for new therapeutic approaches to refractory disease.