Targeted next-generation sequencing of dedifferentiated chondrosarcoma in the skull base reveals combined TP53 and PTEN mutations with increased proliferation index, an implication for pathogenesis

// Lu Gao 1, * , Xiafei Hong 2, * , Xiaopeng Guo 1 , Dengfeng Cao 3 , Xiaohuan Gao 4, 5, 10 , Thomas F. DeLaney 6 , Xinqi Gong 7 , Rongrong Chen 8 , Jianjiao Ni 9 , Yong Yao 1 , Renzhi Wang 1 , Xi Chen 4, 5 , Pangzehuan Tian 4, 5 , Bing Xing 1 1 Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 2 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 3 Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA 4 Binhai Genomics Institute, BGI-Tianjin, Tianjin, China 5 Tianjin Translational Genomics Center, BGI-Tianjin, Tianjin, China 6 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA 7 Institute for Mathematical Sciences, Renmin University of China, Beijing, China 8 Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 9 Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China 10 Department of Cancer Research, Jingke Biotech, Guangzhou, China * These authors have contributed equally to this work Correspondence to: Bing Xing, email: xingbingemail@aliyun.com Keywords: dedifferentiated, chondrosarcoma, TP53 , PTEN , proliferation Received: November 07, 2015      Accepted: May 08, 2016      Published: May 26, 2016 ABSTRACT Dedifferentiated chondrosarcoma (DDCS) is a rare disease with a dismal prognosis. DDCS consists of two morphologically distinct components: the cartilaginous and noncartilaginous components. Whether the two components originate from the same progenitor cells has been controversial. Recurrent DDCS commonly displays increased proliferation compared with the primary tumor. However, there is no conclusive explanation for this mechanism. In this paper, we present two DDCSs in the sellar region. Patient 1 exclusively exhibited a noncartilaginous component with a TP53 frameshift mutation in the pathological specimens from the first surgery. The tumor recurred after radiation therapy with an exceedingly increased proliferation index. Targeted next-generation sequencing (NGS) revealed the presence of both a TP53 mutation and a PTEN deletion in the cartilaginous and the noncartilaginous components of the recurrent tumor. Fluorescence in situ hybridization and immunostaining confirmed reduced DNA copy number and protein levels of the PTEN gene as a result of the PTEN deletion. Patient 2 exhibited both cartilaginous and noncartilaginous components in the surgical specimens. Targeted NGS of cells from both components showed neither TP53 nor PTEN mutations, making Patient 2 a naïve TP53 and PTEN control for comparison. In conclusion, additional PTEN loss in the background of the TP53 mutation could be the cause of increased proliferation capacity in the recurrent tumor.