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Nat Genet. 2018 Oct;50(10):1381-1387. doi: 10.1038/s41588-018-0204-y. Epub 2018 Sep 17.

Mutational processes shape the landscape of TP53 mutations in human cancer.

Author information

1
Dana-Farber Cancer Institute, Boston, MA, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
Harvard Medical School, Boston, MA, USA.
4
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
5
Massachusetts General Hospital Center for Cancer Research, Boston, MA, USA.
6
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
7
Dana-Farber Cancer Institute, Boston, MA, USA. william_hahn@dfci.harvard.edu.
8
Broad Institute of MIT and Harvard, Cambridge, MA, USA. william_hahn@dfci.harvard.edu.
9
Harvard Medical School, Boston, MA, USA. william_hahn@dfci.harvard.edu.
10
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. william_hahn@dfci.harvard.edu.

Abstract

Unlike most tumor suppressor genes, the most common genetic alterations in tumor protein p53 (TP53) are missense mutations1,2. Mutant p53 protein is often abundantly expressed in cancers and specific allelic variants exhibit dominant-negative or gain-of-function activities in experimental models3-8. 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 wild-type p53 function reliably enhanced cellular fitness. By integrating these data with the Catalog of Somatic Mutations in Cancer (COSMIC) mutational signatures database9,10, 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.

PMID:
30224644
PMCID:
PMC6168352
[Available on 2019-03-17]
DOI:
10.1038/s41588-018-0204-y

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