title: Description of a new oncogenic mechanism for atypical teratoid rhabdoid tumors in patients with ring chromosome 22.
abstract: Atypical teratoid rhabdoid tumors of the central nervous system are rare, highly malignant, embryonal tumors most often occurring in children under age 3 years. Most are due to a somatic change in tumor suppressor gene SMARCB1 followed by a second-hit, typically loss of heterozygosity, best detected on immunohistochemical staining. Despite the noteworthy genetic homogeneity of atypical teratoid rhabdoid tumors, relatively little is known about the oncogenic mechanisms that lead to biallelic inactivation of SMARCB1. Herein, we describe a patient with constitutional ring chromosome 22, Phelan-McDermid syndrome and atypical teratoid rhabdoid tumor of the brain. During mitosis, sister chromatids of a ring chromosome may form interlocking and dicentric rings, resulting in chromosomal loss, complex karyotypes, and ongoing somatic variation. We hypothesized that the inherent instability of the patient's ring chromosome could lead to mosaic monosomy chromosome 22, resulting in allelic inactivation of the tumor-suppressor gene SMARCB1 and AT/RT if a second-hit occurred. Utilizing high-density microarray technology to analyze peripheral blood and tumor tissue, we confirmed this oncogenic mechanism, previously undescribed in patients with atypical teratoid rhabdoid tumors. Our data demonstrate chromosomal loss as a consequence of ring chromosome instability serving as the first hit in oncogenesis. This rare but possibly under-recognized mechanism is important to note in children with ATRT and syndromic features. Further investigation is warranted to assess if this oncogenic mechanism has management and/or prognostic implications. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Byers
authors.affiliation: Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Adam
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Amy
authors.initials: A
authors.lastname: LaCroix
authors.affiliation: Division of Oncology, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Sarah E S
authors.initials: SE
authors.lastname: Leary
authors.affiliation: Department of Laboratories, Seattle Children's Hospital, Seattle, Washington.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Cole
authors.affiliation: Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.|Department of Neurology, University of Washington, Seattle, Washington.
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
authors.affiliation: Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000175:diagnosis / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D003131:Combined Modality Therapy; D055028:Comparative Genomic Hybridization; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008279:Magnetic Resonance Imaging; D010641:Phenotype; D018335:Rhabdoid Tumor / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D012303:Ring Chromosomes; D000071796:SMARCB1 Protein / Q000235:genetics / Q000378:metabolism; D013724:Teratoma / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D000071796:SMARCB1 Protein
keywords: AT/RT; INI1; PMS; Phelan-McDermid syndrome; SMARCB1; atypical teratoid rhabdoid tumor; brain tumor; genetics; oncology; ring chromosome