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

Title
High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients
Authors
Cho, Sung-YupPark, ChanghoNa, DeukchaeHan, Jee YunLee, JieunPark, Ok-KyoungZhang, ChengshengSung, Chang OhkMoon, Hyo EunKim, YonaKim, Jeong HoonKim, Jong JaeKhang, Shin KwangNam, Do-HyunChoi, Jung WonSuh, Yeon-LimKim, Dong GyuPark, Sung HyeYoun, HyewonYun, KyusonKim, Jong-IlLee, CharlesPaek, Sun HaPark, Hansoo
Ewha Authors
나득채조성엽
SCOPUS Author ID
조성엽scopus
Issue Date
2017
Journal Title
EXPERIMENTAL AND MOLECULAR MEDICINE
ISSN
1226-3613JCR Link2092-6413JCR Link
Citation
vol. 49
Publisher
NATURE PUBLISHING GROUP
Indexed
SCI; SCIE; SCOPUS; KCI WOS
Abstract
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 (CACNA1s, PLCs and ITPRs) 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.
DOI
10.1038/emm.2017.9
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일반대학원 > 생명과학과 > Journal papers
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