TY - JOUR
T1 - Pre- and Post-Zygotic TP53 De Novo Mutations in SHH-Medulloblastoma.
AU - Azzollini, Jacopo
AU - Schiavello, Elisabetta
AU - Buttarelli, Francesca Romana
AU - Clerici, Carlo Alfredo
AU - Tizzoni, Laura
AU - Vecchi, Giovanna De
AU - Capra, Fabio
AU - Pisati, Federica
AU - Biassoni, Veronica
AU - Runza, Letterio
AU - Carrabba, Giorgio
AU - Giangaspero, Felice
AU - Massimino, Maura
AU - Pensotti, Valeria
AU - Manoukian, Siranoush
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5 showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/CtextgreaterT p.(Arg248=/Trp). The allele frequency was 262-77LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.
AB - Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder caused by mutations in the TP53 gene, predisposing to a wide spectrum of early-onset cancers, including brain tumors. In medulloblastoma patients, the role of TP53 has been extensively investigated, though the prevalence of de novo mutations has not been addressed. We characterized TP53 mutations in a monocentric cohort of consecutive Sonic Hedgehog (SHH)-activated medulloblastoma patients. Germline testing was offered based on tumor p53 immunostaining positivity. Among 24 patients, three (12.5 showed tumor p53 overexpression, of whom two consented to undergo germline testing and resulted as carriers of TP53 mutations. In the first case, family history was uneventful and the mutation was not found in either of the parents. The second patient, with a family history suggestive of LFS, unexpectedly resulted as a carrier of the mosaic mutation c.742=/CtextgreaterT p.(Arg248=/Trp). The allele frequency was 262-77LOH) in the tumor was also confirmed. Notably, the mosaic case has been in complete remission for more than one year, while the first patient, as most TP53-mutated medulloblastoma cases from other cohorts, showed a severe and rapidly progressive disease. Our study reported the first TP53 mosaic mutation in medulloblastoma patients and confirmed the importance of germline testing in p53 overexpressed SHH-medulloblastoma, regardless of family history.
KW - de novo mutation
KW - Li-Fraumeni syndrome
KW - medulloblastoma
KW - somatic mosaicism
KW - TP53
U2 - 10.3390/cancers12092503
DO - 10.3390/cancers12092503
M3 - Article
VL - 12
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 9
ER -