title: SMARCB1/INI1 Involvement in Pediatric Chordoma: A Mutational and Immunohistochemical Analysis.
abstract: Chordomas arise in the skull base and spine and usually occur in adults and are rare in the pediatric population. Cases of chordoma in pediatric age are often poorly differentiated, showing cytologic atypia, increased cellularity, and mitosis, and their aggressive behavior is associated with a high incidence of metastatic spread and a short patient survival. Recent studies have described loss of SMARCB1/INI1 protein in poorly differentiated chordomas associated not with point mutations but with SMARCB1/INI1 gene deletions instead. In this study, we considered immunohistochemistry and SMARCB1/INI1 mutational status to examine SMARCB1 status in a series of pediatric chordomas (7 classic and 1 poorly differentiated). We performed immunohistochemical tests for INI1, brachyury, S100, and cytokeratins and conducted a genetic analysis on the SMARCB1 coding sequence (NM_003073) using the Sanger method and multiplex ligation-dependent probe amplification to detect abnormal copy numbers of the gene locus. All 8 cases were positive for brachyury, whereas there was no nuclear SMARCB1/INI1 expression in 4 of the 8 cases, including the poorly differentiated chordoma. Genetic analysis identified a missense mutation in 2 cases and a nonsense mutation associated with loss of SMARCB1/INI1 protein and features of poorly differentiated tumor in 1. These mutations were novel variants occurring in heterozygosity, and they were judged to be pathogenic by 3 different bioinformatic tools. In 7 of 8 cases we performed multiplex ligation-dependent probe amplification, and 3 cases showed deletions at the SMARCB1 locus. Our results confirm the pathogenic involvement of SMARCB1/INI1 in childhood chordoma. We also describe 3 novel pathogenic mutations.
authors.affiliation: *Department of Radiological, Oncological and Anatomo-Pathological Sciences **Department of Neurological Sciences, Sapienza University §Institute of Pathology, Catholic University, Rome †Dipartimento Testa-Collo e Neuroscienze, Istituto Giannina Gaslini, Genoa ∥Department of Surgical Oncological and Gastroenterological Sciences, Urology University of Padova, Padova ¶IRCCS Neuromed, Pozzilli (IS) #Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy ‡Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Manila
authors.initials: M
authors.lastname: Antonelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Raso
authors.forename: Samantha
authors.initials: S
authors.lastname: Mascelli
authors.forename: Marco
authors.initials: M
authors.lastname: Gessi
authors.forename: Paolo
authors.initials: P
authors.lastname: Nozza
authors.forename: Antonella
authors.initials: A
authors.lastname: Coli
authors.forename: Marina P
authors.initials: MP
authors.lastname: Gardiman
authors.forename: Antonietta
authors.initials: A
authors.lastname: Arcella
authors.forename: Maura
authors.initials: M
authors.lastname: Massimino
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Buttarelli
authors.forename: Felice
authors.initials: F
authors.lastname: Giangaspero
mesh_terms: D000293:Adolescent; D002648:Child; D002817:Chordoma / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D000071796:SMARCB1 Protein / Q000235:genetics*; D019292:Skull Base Neoplasms / Q000235:genetics*; D013125:Spinal Neoplasms / Q000235:genetics*
chemical_list: D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human