Novel oncogene amplifications in tumors from a family with Li-Fraumeni syndrome.
Li-Fraumeni syndrome (LFS) represents an inherited tumor syndrome that is typically caused by germline mutations of the tumor suppressor gene TP53. TP53 dysfunction secondarily disturbs the genetic integrity of the cell. Here, we report a family with LFS harboring a germline TP53 mutation (R248W) located in the functional domain of the protein that binds to the minor groove of the DNA. In this family, tumors of the central nervous system were diagnosed as primary malignancies in all carriers of the mutation. The index patient developed an anaplastic medulloblastoma with unusual genomic profile exhibiting six distinct high-level genomic amplifications, two of them targeting the MYCN and GLI2 genes, respectively. In an extrarenal rhabdoid tumor from the same patient, we found a novel high-level amplification of the MYC oncogene. The father of this patient was diagnosed with myxopapillary ependymoma (WHO degrees I), whereas a brother died from an early relapse of a choroid plexus carcinoma. The analysis of this LFS familiy thus revealed novel oncogene amplifications as different second hits that are likely to also play a role in the pathogenesis of their sporadic counterparts.
Rieber
Juliane
J
Division Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
Remke
Marc
M
Hartmann
Christian
C
Korshunov
Andrey
A
Burkhardt
Birgit
B
Sturm
Dominik
D
Mechtersheimer
Gunhild
G
Wittmann
Andrea
A
Greil
Johann
J
Blattmann
Claudia
C
Witt
Olaf
O
Behnisch
Wolfgang
W
Halatsch
Marc-Eric
ME
Orakcioglu
Berk
B
von Deimling
Andreas
A
Lichter
Peter
P
Kulozik
Andreas
A
Pfister
Stefan
S
D002648:Child; D016545:Choroid Plexus Neoplasms / Q000235:genetics / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D018335:Rhabdoid Tumor / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53