Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.
Truncation- and motif-based pan-cancer analysis reveals tumor-suppressing kinases.
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基于截短和基序的泛伴侣分析揭示了肿瘤抑制的激酶。
DOI：
10.1126/scisignal.aan6776
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发表时间：
2018-04-17
影响因子：
7.3
通讯作者：
Brognard J
中科院分区：
文献类型：
--
作者：
Hudson AM;Stephenson NL;Li C;Trotter E;Fletcher AJ;Katona G;Bieniasz-Krzywiec P;Howell M;Wirth C;Furney S;Miller CJ;Brognard J
A major challenge in cancer genomics is identifying “driver” mutations from the many neutral “passenger” mutations within a given tumor. To identify driver mutations that would otherwise be lost within mutational noise, we filtered genomic data by motifs that are critical for kinase activity. In the first step of our screen, we used data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas to identify kinases with truncation mutations occurring within or before the kinase domain. The top 30 tumor-suppressing kinases were aligned, and hotspots for loss-of-function (LOF) mutations were identified on the basis of amino acid conservation and mutational frequency. The functional consequences of new LOF mutations were biochemically validated, and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7, an essential mediator of the c-Jun N-terminal kinase (JNK) pathway, as a candidate tumor suppressor in gastric cancer, despite its mutational frequency falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished its catalytic activity, and reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or the downstream kinase JNK suppressed clonogenicity and growth in soft agar, demonstrating the functional relevance of inactivating the JNK pathway in gastric cancer. Together, our data highlight a broadly applicable strategy to identify functional cancer driver mutations and define the JNK pathway as tumor-suppressive in gastric cancer.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
5.7
作者：
Sakai H;Sato A;Aihara Y;Ikarashi Y;Midorikawa Y;Kracht M;Nakagama H;Okamoto K
通讯作者：
Okamoto K
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
64.5
作者：
Creixell P;Schoof EM;Simpson CD;Longden J;Miller CJ;Lou HJ;Perryman L;Cox TR;Zivanovic N;Palmeri A;Wesolowska-Andersen A;Helmer-Citterich M;Ferkinghoff-Borg J;Itamochi H;Bodenmiller B;Erler JT;Turk BE;Linding R
通讯作者：
Linding R
影响因子：
13.8
作者：
Taylor, Susan S.;Kornev, Alexandr P.
通讯作者：
Kornev, Alexandr P.