Mutational processes shape the landscape of TP53 mutations in human cancer.
Mutational processes shape the landscape of TP53 mutations in human cancer.
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DOI：
10.1038/s41588-018-0204-y
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发表时间：
2018-10
期刊：
影响因子：
30.8
通讯作者：
Hahn WC
中科院分区：
文献类型：
--
作者：
Giacomelli AO;Yang X;Lintner RE;McFarland JM;Duby M;Kim J;Howard TP;Takeda DY;Ly SH;Kim E;Gannon HS;Hurhula B;Sharpe T;Goodale A;Fritchman B;Steelman S;Vazquez F;Tsherniak A;Aguirre AJ;Doench JG;Piccioni F;Roberts CWM;Meyerson M;Getz G;Johannessen CM;Root DE;Hahn WC
Unlike most tumor suppressor genes, the most common genetic alterations in TP53 are missense mutations. Mutant p53 protein is often abundantly expressed in cancers, and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models. To gain a systematic view of p53 function, we interrogated loss-of-function screens conducted in hundreds of human cancer cell lines and performed TP53 saturation mutagenesis screens in an isogenic pair of TP53-wild-type and -null cell lines. We found that loss or dominant-negative inhibition of p53 function reliably enhanced cellular fitness. By integrating these data with the COSMIC mutational signatures database, we developed a statistical model that describes the TP53 mutational spectrum as a function of the baseline probability of acquiring each mutation and the fitness advantage conferred by attenuation of p53 activity. Collectively, these observations show that widely-acting and tissue-specific mutational processes combine with phenotypic selection to dictate the frequencies of recurrent TP53 mutations.
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影响因子：
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van Steensel B
影响因子：
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通讯作者：
Benes, Cyril H.