SMARCB1-deficient and SMARCA4-deficient Malignant Brain Tumors with Complex Copy Number Alterations and TP53 Mutations May Represent the First Clinical Manifestation of Li-Fraumeni Syndrome

Martin Hasselblatt, Christian Thomas, Aniello Federico, Karolina Nemes, Pascal D. Johann, Brigitte Bison, Susanne Bens, Sonja Dahlum, Uwe Kordes, Antje Redlich, Lienhard Lessel, Kristian W. Pajtler, Christian Mawrin, Ulrich Schüller, Kay Nolte, Christof M. Kramm, Felix Hinz, Felix Sahm, Caterina Giannini, Judith PenkertChristian P. Kratz, Stefan M. Pfister, Reiner Siebert, Werner Paulus, Marcel Kool, Michael C. Frühwald

Research output: Contribution to journalArticlepeer-review

Abstract

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations ofSMARCB1or (rarely)SMARCA4causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising from other central nervous system tumors have been reported. Malignant gliomas, IDH wild-type, arising in patients with Li-Fraumeni syndrome typically show somatic mutations ofTP53as well as complex copy number alterations, but little is known about the loss of SMARCB1 or SMARCA4 protein expression in this context. Here, we report 2 children in whom malignant supratentorial brain tumors with SMARCB1 deficiency, complex copy number alterations, and somaticTP53mutations lead to the discovery of pathogenic/likely pathogenicTP53variants in the germline. Screening of the molecularneuropathology.org dataset for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4 deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1-deficient or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somaticTP53mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation forTP53germline status.

Original languageEnglish (US)
JournalAmerican Journal of Surgical Pathology
DOIs
StateAccepted/In press - 2022

Keywords

  • atypical teratoid/rhabdoid tumor
  • DNA methylation profiling
  • germline
  • SMARCA4/Brg1
  • SMARCB1/INI1
  • TP53

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Fingerprint

Dive into the research topics of 'SMARCB1-deficient and SMARCA4-deficient Malignant Brain Tumors with Complex Copy Number Alterations and TP53 Mutations May Represent the First Clinical Manifestation of Li-Fraumeni Syndrome'. Together they form a unique fingerprint.

Cite this