Cdkn2a suppresses metastasis in squamous cell carcinomas induced by the gain-of-function mutant p53(R172H).
Cdkn2a suppresses metastasis in squamous cell carcinomas induced by the gain-of-function mutant p53(R172H).
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DOI：
10.1002/path.4770
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Caulin C
中科院分区：
文献类型：
--
作者：
Li Z;Gonzalez CL;Wang B;Zhang Y;Mejia O;Katsonis P;Lichtarge O;Myers JN;El-Naggar AK;Caulin C
p53 is the most frequently mutated gene in squamous cell carcinomas (SCCs) of the skin and head and neck. Certain p53 mutations are oncogenic and promote invasion and metastasis in SCCs. However, it is unclear how the oncogenic function of mutant p53 is modulated by other molecular alterations that co-exist in SCCs. Here, we show that deletion of the p53 gene and activation of an endogenous p53R172H gain-of-function mutation in the skin induce carcinomas with similar kinetics and penetrance. Deletion of p53 induced primarily well differentiated SCCs. However, most of the tumors induced by p53R172H were poorly differentiated SCCs, the only metastatic tumors in this model. These tumors expressed higher levels of Cyclin D1 than the well differentiated SCCs and spindle carcinomas that developed in these mice. Unexpectedly, metastasis was not observed in mice that developed spindle carcinomas, which expressed high levels of the tumor suppressors p16Ink4a and p19Arf, encoded by Cdkn2a, a gene frequently deleted in human SCCs. Remarkably, deletion of the Cdkn2a gene in p53R172H-induced SCCs promoted a dramatic increase in metastasis rates and a shorter survival in mice that developed these tumors, compared with those observed in mice with tumors in which Cdkn2a was deleted in the presence of a p53 loss-of-function mutation or wild-type p53. Accordingly, the survival of patients with head and neck SCCs bearing co-occurring high-risk p53 mutations and CDKN2A homozygous deletions was much shorter than that of patients with tumors in which high-risk p53 mutations did not contain CDKN2A homozygous deletions, or that of patients with tumors in which homozygous CDKN2A deletions co-existed with either low-risk p53 mutations or potential loss-of-function mutations in p53. These findings genetically identify a population of SCC patients with worst outcomes and will help predict outcomes according to the p53 status and alterations in CDKN2A.
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DOI：
10.1158/1078-0432.ccr-14-1773
发表时间：
2015-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Li YY;Hanna GJ;Laga AC;Haddad RI;Lorch JH;Hammerman PS
通讯作者：
Hammerman PS
DOI：
10.1073/pnas.91.1.360
发表时间：
1994-01-04
影响因子：
11.1
作者：
NAKAZAWA, H;ENGLISH, D;YAMASAKI, H
通讯作者：
YAMASAKI, H
影响因子：
158.5
作者：
Poeta, M. Luana;Manola, Judith;Koch, Wayne M.
通讯作者：
Koch, Wayne M.
影响因子：
30.8
作者：
Jonkers, J;Meuwissen, R;Berns, A
通讯作者：
Berns, A
影响因子：
30.8
作者：
DITTMER, D;PATI, S;LEVINE, AJ
通讯作者：
LEVINE, AJ