High Frequency of Germline SUFU Mutations in Children With Desmoplastic/Nodular Medulloblastoma Younger Than 3 Years of Age
ABSTRACT Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations.
A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available.
We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient.
These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog-driven medulloblastoma at a young age.
- SourceAvailable from: Scott L Pomeroy
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- "Moreover, all four MBs with extensive nodularity (MBEN) were found in infants (Figures 3A and 3B). In contrast to a recent report (Brugiè res et al., 2012), which was, however, reporting on a larger number of MBEN MBs, only 1/4 MBEN cases in our series had an SUFU mutation, while two harbored a PTCH1, and one displayed an SMO mutation (Figure 3A). "
ABSTRACT: Smoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.Cancer cell 03/2014; 25(3):393-405. DOI:10.1016/j.ccr.2014.02.004 · 23.52 Impact Factor
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ABSTRACT: Many tumors have alterations in molecular pathways linked to embryogenesis. The sonic hedgehog pathway is one of the best known, and mutations in some of its components have an important role in tumors such as basal cell carcinoma and medulloblastoma. On the other hand, a role of paracrine in tumorÁmicroenviroment relationship has been described in a broad spectrum of malignancies (ie, colon, ovary, breast, pancreatic and lung cancer). In the present work, we review the molecular biology of the sonic hedgehog pathway, its role in carcinogenesis, and the development of targeted treatments against it.
- Journal of Clinical Oncology 04/2012; 30(17):2154-6. DOI:10.1200/JCO.2011.41.1181 · 18.43 Impact Factor