Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants.
Phenotypic Characterization of a Comprehensive Set of MAPK1/ERK2 Missense Mutants.
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DOI：
10.1016/j.celrep.2016.09.061
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发表时间：
2016-10-18
期刊：
影响因子：
8.8
通讯作者：
Johannessen CM
中科院分区：
文献类型：
--
作者：
Brenan L;Andreev A;Cohen O;Pantel S;Kamburov A;Cacchiarelli D;Persky NS;Zhu C;Bagul M;Goetz EM;Burgin AB;Garraway LA;Getz G;Mikkelsen TS;Piccioni F;Root DE;Johannessen CM
肿瘤特异性基因组信息具有指导治疗策略和彻底改变患者治疗的潜力。目前，这种方法受到大量疾病相关突变体的限制，这些突变体的生物学功能和对治疗反应的影响尚不清楚。为了开始解决这一限制，我们在功能上表征了几乎所有（99.84%）MAPK 1/ERK 2错义突变体，MAPK 1/ERK 2是致癌RAS和RAF的重要效应子。使用这种方法，我们发现了在人类肿瘤中发现的罕见的功能获得和功能丧失的ERK 2突变体，这表明，在这种测定的背景下，单独的突变频率不能识别所有功能上有影响的突变体。功能获得性ERK 2突变体诱导对RAF、MEK和ERK导向疗法的可变应答，为未来的治疗决策提供参考。肿瘤相关突变在空间上聚集在两个ERK 2效应募集结构域，但产生具有相反表型的突变体。这种方法阐明了一个等位基因表征框架，可以扩展以满足基因组指导肿瘤学的目标。
Tumor-specific genomic information has the potential to guide therapeutic strategies and revolutionize patient treatment. Currently, this approach is limited by an abundance of disease-associated mutants whose biological functions and impacts on therapeutic response are uncharacterized. To begin to address this limitation, we functionally characterized nearly all (99.84%) missense mutants of MAPK1/ERK2, an essential effector of oncogenic RAS and RAF. Using this approach, we discovered rare gain- and loss-of-function ERK2 mutants found in human tumors, revealing that, in the context of this assay, mutational frequency alone cannot identify all functionally impactful mutants. Gain-of-function ERK2 mutants induced variable responses to RAF-, MEK- and ERK-directed therapies, providing a reference for future treatment decisions. Tumor-associated mutations spatially clustered in two ERK2 effector-recruitment domains, yet produced mutants with opposite phenotypes. This approach articulates an allele-characterization framework that can be scaled to meet the goals of genome-guided oncology.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Berger AH;Brooks AN;Wu X;Shrestha Y;Chouinard C;Piccioni F;Bagul M;Kamburov A;Imielinski M;Hogstrom L;Zhu C;Yang X;Pantel S;Sakai R;Watson J;Kaplan N;Campbell JD;Singh S;Root DE;Narayan R;Natoli T;Lahr DL;Tirosh I;Tamayo P;Getz G;Wong B;Doench J;Subramanian A;Golub TR;Meyerson M;Boehm JS
通讯作者：
Boehm JS
影响因子：
11.2
作者：
Goetz EM;Ghandi M;Treacy DJ;Wagle N;Garraway LA
通讯作者：
Garraway LA
DOI：
10.1073/pnas.1417571112
发表时间：
2015-03-03
影响因子：
11.1
作者：
Alexa, Anita;Gogl, Gergo;Remenyi, Attila
通讯作者：
Remenyi, Attila