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Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition
Cancer cell, 2014-03, Vol.25 (3), p.393-405
2014
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Details

Autor(en) / Beteiligte
Titel
Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition
Ist Teil von
  • Cancer cell, 2014-03, Vol.25 (3), p.393-405
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2014
Quelle
Elsevier ScienceDirect Journals
Beschreibungen/Notizen
  • 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. [Display omitted] •SHH-MBs in infants, children, and adults are genomically distinct from each other•Most adult, but only half of the pediatric, SHH-MBs will respond to SMO inhibition•Tumor predisposition (PTCH1, SUFU, TP53) is highly prevalent in pediatric SHH-MB•Recurrent mutations outside the SHH-pathway suggest rational combination therapies Smoothened (SMO) inhibitors are in clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB), but response varies. By profiling a large SHH-MB cohort, Kool et al. reveal age-dependent genomic distinction and demonstrate genotype-related response to SMO inhibition using patient-derived xenograft cells.
Sprache
Englisch
Identifikatoren
ISSN: 1535-6108
eISSN: 1878-3686
DOI: 10.1016/j.ccr.2014.02.004
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4493053
Format
–
Schlagworte
Adolescent, Adult, Animals, Base Sequence, Biphenyl Compounds - therapeutic use, Cerebellar Neoplasms - drug therapy, Cerebellar Neoplasms - genetics, Child, Child, Preschool, DEAD-box RNA Helicases - genetics, DNA Copy Number Variations - genetics, Drug Resistance, Neoplasm - genetics, Female, Gene Expression Profiling, Hedgehog Proteins - genetics, High-Throughput Nucleotide Sequencing, Humans, Infant, Kruppel-Like Transcription Factors - genetics, Male, Medulloblastoma - drug therapy, Medulloblastoma - genetics, Mice, Mice, Inbred NOD, Mice, SCID, Molecular Sequence Data, N-Myc Proto-Oncogene Protein, Neoplasm Transplantation, Nuclear Proteins - genetics, Oncogene Proteins - genetics, Patched Receptors, Patched-1 Receptor, Phosphatidylinositol 3-Kinases - genetics, Phosphatidylinositol 3-Kinases - metabolism, Promoter Regions, Genetic - genetics, Proto-Oncogene Proteins c-akt - genetics, Proto-Oncogene Proteins c-akt - metabolism, Pyridines - therapeutic use, Receptors, Cell Surface - genetics, Receptors, G-Protein-Coupled - antagonists & inhibitors, Receptors, G-Protein-Coupled - genetics, Repressor Proteins - genetics, Signal Transduction - genetics, Smoothened Receptor, Telomerase - genetics, Tumor Suppressor Protein p53 - genetics, Young Adult, Zinc Finger Protein Gli2

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