Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

Liu, Y., Chen, C., Xu, Z., Scuoppo, C., Rillahan, C. D., Gao, J., Spitzer, B., Bosbach, B., Kastenhuber, E. R., Baslan, T., Ackermann, S., Cheng, L., Wang, Q., Niu, T., Schultz, N., Levine, R. L., Mills, A. A., Lowe, S. W. (March 2016) Deletions linked to TP53 loss drive cancer through p53-independent mechanisms. Nature, 531 (7595). pp. 471-475. ISSN 1476-4687 (Electronic)0028-0836 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/26982726
DOI: 10.1038/nature17157

Abstract

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.

Item Type: Paper
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > tumor suppressor
CSHL Authors:
Communities: CSHL labs > Mills lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 24 March 2016
Date Deposited: 22 Mar 2016 14:23
Last Modified: 06 Mar 2018 20:58
PMCID: PMC4836395
Related URLs:
URI: http://repository.cshl.edu/id/eprint/32450

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