Description of a new oncogenic mechanism for atypical teratoid rhabdoid tumors in patients with ring chromosome 22

Heather M. Byers, Margaret P. Adam, Amy LaCroix, Sarah E.S. Leary, Bonnie Cole, William B. Dobyns, Heather C. Mefford

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)245-249
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Issue number1
StatePublished - Jan 1 2017
Externally publishedYes

Bibliographical note

Funding Information:
We thank the patient's family for their participation. We also thank Dr. Karen Tsuchiya at Seattle Children's Hospital. Heather Byers is supported by NIH 5T32GM007454.

Publisher Copyright:
© 2016 Wiley Periodicals, Inc.


  • AT/RT
  • INI1
  • PMS
  • Phelan–McDermid syndrome
  • atypical teratoid rhabdoid tumor
  • brain tumor
  • genetics
  • oncology
  • ring chromosome


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