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Cold Spring Harb Mol Case Stud. 2018 Apr 2;4(2). pii: a002246. doi: 10.1101/mcs.a002246. Print 2018 Apr.

Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma.

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Department of Pediatrics, Tampere University Hospital, FI-33521 Tampere, Finland.
Tampere Center for Child Health Research, University of Tampere, FI-33014 Tampere, Finland.
Unit of Neurosurgery, Tampere University Hospital, FI-33521 Tampere, Finland.
BioMediTech Institute and Faculty of Medicine and Life Sciences, University of Tampere, FI-33520 Tampere, Finland.
Laboratory of Cancer Genetics, University of Tampere and Tampere University Hospital, FI-33521 Tampere, Finland.
Science Center, Tampere University Hospital, FI-33521 Tampere, Finland.
Fimlab Laboratories Limited, Tampere University Hospital, FI-33520 Tampere, Finland.


Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with the loss of ATRX protein expression. In the astrocytoma case, R132C missense mutation was found in the known hotspot site in isocitrate dehydrogenase 1 (IDH1) and LOH was detected in TP53 The mother carried few other somatic alterations, suggesting that the IDH1 mutation and LOH in TP53 were sufficient to drive tumor development. The genome in the AT/RT tumor was atypically aneuploid: Most chromosomes had experienced copy-neutral LOH or whole-chromosome gains. Only Chromosome 18 had normal diploid status. INI1/hSNF5/SMARCB1 was homozygously deleted in the AT/RT tumor. This report provides further information about tumor development in a predisposed genetic background and describes two special Li-Fraumeni cases with a familial brain tumor.


neoplasm of the central nervous system

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