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000277733 1001_ $$0P:(DE-He78)3fdc3623477264cb5d0e14f256dbfbb8$$aJohann, Pascal$$b0$$eFirst author$$udkfz
000277733 245__ $$aRecurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics.
000277733 260__ $$aHeidelberg$$bSpringer$$c2023
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000277733 500__ $$a#EA:B062# / 2023 Sep;146(3):527-541
000277733 520__ $$aAtypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences.
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000277733 650_7 $$2Other$$aAT/RT
000277733 650_7 $$2Other$$aDNA methylation
000277733 650_7 $$2Other$$aPediatric cancer
000277733 650_7 $$2Other$$aRNA sequencing
000277733 650_7 $$2Other$$aRecurrent tumor
000277733 650_7 $$2Other$$aRhabdoid tumor
000277733 7001_ $$aAltendorf, Lea$$b1
000277733 7001_ $$aEfremova, Emma-Maria$$b2
000277733 7001_ $$aHolsten, Till$$b3
000277733 7001_ $$aSteinbügl, Mona$$b4
000277733 7001_ $$aNemes, Karolina$$b5
000277733 7001_ $$aEckhardt, Alicia$$b6
000277733 7001_ $$aKresbach, Catena$$b7
000277733 7001_ $$aBockmayr, Michael$$b8
000277733 7001_ $$aKoch, Arend$$b9
000277733 7001_ $$aHaberler, Christine$$b10
000277733 7001_ $$aAntonelli, Manila$$b11
000277733 7001_ $$aDeSisto, John$$b12
000277733 7001_ $$aSchuhmann, Martin U$$b13
000277733 7001_ $$aHauser, Peter$$b14
000277733 7001_ $$aSiebert, Reiner$$b15
000277733 7001_ $$aBens, Susanne$$b16
000277733 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b17$$udkfz
000277733 7001_ $$aGreen, Adam L$$b18
000277733 7001_ $$aHasselblatt, Martin$$b19
000277733 7001_ $$aFrühwald, Michael C$$b20
000277733 7001_ $$00000-0002-8731-1121$$aSchüller, Ulrich$$b21
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