Exp Mol Med.
2017 Apr;49(4):e317. 10.1038/emm.2017.9.
High prevalence of TP53 mutations is associated with poor survival and an EMT signature in gliosarcoma patients
- Cho SY
- Park C
- Na D
- Han JY
- Lee J
- Park OK
- Zhang C
- Sung CO
- Moon HE
- Kim Y
- Kim JH
- Kim JJ
- Khang SK
- Nam DH
- Choi JW
- Suh YL
- Kim DG
- Park SH
- Youn H
- Yun K
- Kim JI
- Lee C
- Paek SH
- Park H
- Affiliations
-
- 1Ewha Institute of Convergence Medicine, Ewha Womans University Mokdong Hospital, Seoul, Korea.
- 2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
- 3Department of Life Science, Ewha Womans University, Seoul, Korea.
- 4The Jackson Laboratory for Genomic Medicine, Farmington, IL, USA.
- 5Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
- 6Department of Neurosurgery, Seoul National University College of Medicine, Seoul, Korea. paeksh@snu.ac.kr
- 7Department of Neurosurgery, Seoul National University Hospital, Seoul, Korea.
- 8Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
- 9Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
- 10Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
- 11Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
- 12Department of Pathology, Seoul National University Hospital, Seoul, Korea.
- 13Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
- 14Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Korea.
- 15The Jackson Laboratory, Bar Harbor, ME, USA.
- 16Medical Research Center, Genomic Medicine Institute (GMI), Seoul National University, Seoul, Korea.
- 17Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea. hspark27@gist.ac.kr
- KMID: 2382708
- DOI: http://doi.org/10.1038/emm.2017.9
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.
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