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

Abstract

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing 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 of TP53 as 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 somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants 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 somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.

Genome-Wide Identification and Characterization of the BRD Family in Nile Tilapia (Oreochromis niloticus)

“…Interestingly, brpf3b was the most highly expressed gene in the tilapia kidney, suggesting it may affect kidney development. Smarca4 , a highly expressed gene in tilapia brain tissue, was shown to play an important role in the development of child brain stems [ 60 , 61 ]. Zmynd8 , a gene preferentially expressed in the tilapia brain, plays an important role in Xenopus neural differentiation [ 62 ].…”

Current Molecular and Clinical Landscape of ATRT – The Link to Future Therapies

“…Histopathologic differential diagnoses in the scope of SMARCB1 -deficient tumor entities are listed in Table 1 and comprise LGDIT, 13 desmoplastic myxoid tumor, SMARB1 -mutant, 14 , 15 CRINET, 16 , 17 PXA, 18 or SMARCB1 -deficient malignant tumors in the context of Li-Fraumeni syndrome. 19 …”

“…Histopathologic differential diagnoses in the scope of SMARCB1-deficient tumor entities are listed in Table 1 and comprise LGDIT, 13 desmoplastic myxoid tumor, SMARB1-mutant, 14,15 CRINET, 16,17 PXA, 18 or SMARCB1-deficient malignant tumors in the context of Li-Fraumeni syndrome. 19 ATRT Exhibit Uniform Inactivation of SMARCB1 or SMARCA4 but Comprise Distinct Molecular Subgroups components, rhabdoid cells, small round blue cells 5,20 Supratentorial, infratentorial and (less common)…”

Artificial intelligence platform, RADR®, aids in the discovery of DNA damaging agent for the ultra-rare cancer Atypical Teratoid Rhabdoid Tumors

“…There are prominent examples of cancers with loss-offunction somatic gene mutations in the SWI/SNF chromatin remodeling complex, including atypical teratoid rhabdoid tumors (ATRT), caused by mutations in SMARCB1, and various additional rhabdoid tumors, that harbor mutations in SMARCA4 (Holdhof et al, 2021;Hasselblatt et al, 2022). In addition to these cancer types, the NCI-60 mutation data were checked to examine if there were any cell lines with mutations in SMARCB1 or SMARCA4.…”