High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients

Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome seq...

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Published in:Experimental & molecular medicine Vol. 49; no. 4; p. e317
Main Authors: Cho, Sung-Yup, Park, Changho, Na, Deukchae, Han, Jee Yun, Lee, Jieun, Park, Ok-Kyoung, Zhang, Chengsheng, Sung, Chang Ohk, Moon, Hyo Eun, Kim, Yona, Kim, Jeong Hoon, Kim, Jong Jae, Khang, Shin Kwang, Nam, Do-Hyun, Choi, Jung Won, Suh, Yeon-Lim, Kim, Dong Gyu, Park, Sung Hye, Youn, Hyewon, Yun, Kyuson, Kim, Jong-Il, Lee, Charles, Paek, Sun Ha, Park, Hansoo
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01-04-2017
Springer Nature B.V
Nature Publishing Group
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Summary:Gliosarcoma (GS) is a rare variant (2%) of glioblastoma (GBM) that poses clinical genomic challenges because of its poor prognosis and limited genomic information. To gain a comprehensive view of the genomic alterations in GS and to understand the molecular etiology of GS, we applied whole-exome sequencing analyses for 28 GS cases (6 blood-matched fresh-frozen tissues for the discovery set, 22 formalin-fixed paraffin-embedded tissues for the validation set) and copy-number variation microarrays for 5 blood-matched fresh-frozen tissues. TP53 mutations were more prevalent in the GS cases (20/28, 70%) compared to the GBM cases (29/90, 32%), and the GS patients with TP53 mutations showed a significantly shorter survival (multivariate Cox analysis, hazard ratio=23.9, 95% confidence interval, 2.87–199.63, P =0.003). A pathway analysis showed recurrent alterations in MAPK signaling ( EGFR , RASGRF2 and TP53 ), phosphatidylinositol/calcium signaling ( CACNA1 s, PLC s and ITPR s) and focal adhesion/tight junction ( PTEN and PAK3 ) pathways. Genomic profiling of the matched recurrent GS cases detected the occurrence of TP53 mutations in two recurrent GS cases, which suggests that TP53 mutations play a role in treatment resistance. Functionally, we found that TP53 mutations are associated with the epithelial–mesenchymal transition (EMT) process of sarcomatous components of GS. We provide the first comprehensive genome-wide genetic alternation profiling of GS, which suggests novel prognostic subgroups in GS patients based on their TP53 mutation status and provides new insight in the pathogenesis and targeted treatment of GS. Brain cancer: A deadly driver for gliosarcoma Genetic analysis of gliosarcoma samples reveals mutations that contribute to more aggressive tumor growth and a worse prognosis. This form of brain cancer is very rare, and the biological factors that drive its growth are poorly understood. Researchers led by Hansoo Park of GIST (Gwangju Institute of Science and Technology) and Sun Ha Paek at Seoul National University analyzed 28 patient samples and found one gene with an apparently critical role. They found that 71% of the tumors tested contained mutations in TP53, a gene that normally prevents cancerous growth. Patients with these mutations had worse prognoses, and alterations in TP53 were repeatedly observed in tumors that recurred after chemotherapy. The researchers determined that these TP53 mutations initiate cellular processes that favor aggressive and invasive growth, potentially explaining the worse prognoses in affected patients.
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These authors contributed equally to this work.
These authors contributed equally to this work and are considered co-first authors.
These authors share senior authorship of this article.
ISSN:2092-6413
1226-3613
2092-6413
DOI:10.1038/emm.2017.9