title: Integrated genomics has identified a new AT/RT-like yet INI1-positive brain tumor subtype among primary pediatric embryonal tumors.
abstract: BACKGROUND
  Pediatric embryonal brain tumors (PEBTs), which encompass medulloblastoma (MB), primitive neuroectodermal tumor (PNET) and atypical teratoid/rhabdoid tumor (AT/RT), are the second most prevalent pediatric brain tumor type. AT/RT is highly malignant and is often misdiagnosed as MB or PNET. The distinction of AT/RT from PNET/MB is of clinical significance because the survival rate of patients with AT/RT is substantially lower. The diagnosis of AT/RT relies primarily on morphologic assessment and immunohistochemical (IHC) staining for a few known markers such as the lack of INI1 protein expression. However, in our clinical practice we have observed several AT/RT-like tumors, that fulfilled histopathological and all other biomarker criteria for a diagnosis of AT/RT, yet retained INI1 immunoreactivity. Recent studies have also reported preserved INI1 immunoreactivity among certain diagnosed AT/RTs. It is therefore necessary to re-evaluate INI1(+), AT/RT-like cases.
  
  
  METHODS
  Sanger sequencing, array CGH and mRNA microarray analyses were performed on PEBT samples to investigate their genomic landscapes.
  
  
  RESULTS
  Patients with AT/RT and those with INI(+) AT/RT-like tumors showed a similar survival rate, and global array CGH analysis and INI1 gene sequencing showed no differential chromosomal aberration markers between INI1(-) AT/RT and INI(+) AT/RT-like cases. We did not misdiagnose MBs or PNETs as AT/RT-like tumors because transcriptome profiling revealed that not only did AT/RT and INI(+) AT/RT-like cases express distinct mRNA and microRNA profiles, their gene expression patterns were different from those of MBs and PNETs. The most similar transcriptome profile to that of AT/RTs was the profile of embryonic stem cells. However; the transcriptome profile of INI1(+) AT/RT-like tumors was more similar to that of somatic neural stem cells, while the profile of MBs was closer to that of fetal brain tissue. Novel biomarkers were identified that can be used to distinguish INI1(-) AT/RTs, INI1(+) AT/RT-like cases and MBs.
  
  
  CONCLUSIONS
  Our studies revealed a novel INI1(+) ATRT-like subtype among Taiwanese pediatric patients. New diagnostic biomarkers, as well as new therapeutic tactics, can be developed according to the transcriptome data that were unveiled in this work.
authors.affiliation: Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. mtho@vghtpe.gov.tw.|School of Medicine, National Yang-Ming University, Taipei, Taiwan. mtho@vghtpe.gov.tw.
authors.forename: Donald Ming-Tak
authors.initials: DM
authors.lastname: Ho
authors.affiliation: Department of Obstetrics and Gynecology, Hsin-Chu Mackay Memorial Hospital, Hsin Chu, Taiwan. shihmd0316@yahoo.com.
authors.forename: Chuan-Chi
authors.initials: CC
authors.lastname: Shih
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. mlliang@vghtpe.gov.tw.|Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. mlliang@vghtpe.gov.tw.
authors.forename: Muh-Lii
authors.initials: ML
authors.lastname: Liang
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. chanyentw@yahoo.com.tw.
authors.forename: Chan-Yen
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. thhsieh2003@gmail.com.|Department of Neurosurgery Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. thhsieh2003@gmail.com.
authors.forename: Tsung-Han
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: Department of Obstetrics and Gynecology, Hsin-Chu Mackay Memorial Hospital, Hsin Chu, Taiwan. 4487@mmh.org.tw.
authors.forename: Chin-Han
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. diegolin@vghtpe.gov.tw.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. taiwanbird@gmail.com.
authors.forename: Ting-Yu
authors.initials: TY
authors.lastname: Chang
authors.affiliation: Department of Neurosurgery Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. chaomengen@gmail.com.
authors.forename: Meng-En
authors.initials: ME
authors.lastname: Chao
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan. hwwang@ym.edu.tw.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan. hwwang@ym.edu.tw.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan. hwwang@ym.edu.tw.|Department of Education and Research, Taipei City Hospital, Taipei, Taiwan. hwwang@ym.edu.tw.
authors.forename: Hsei-Wei
authors.initials: HW
authors.lastname: Wang
authors.affiliation: Genome Research Center, National Yang-Ming University, Taipei, Taiwan. ttwong99@gmail.com.|Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. ttwong99@gmail.com.|Department of Neurosurgery Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan. ttwong99@gmail.com.
authors.forename: Tai-Tong
authors.initials: TT
authors.lastname: Wong
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009373:Neoplasms, Germ Cell and Embryonal / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology; D011379:Prognosis; D018335:Rhabdoid Tumor / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000071796:SMARCB1 Protein; D013724:Teratoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors