Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition

Cancer Cell. 2014 Mar 17;25(3):393-405. doi: 10.1016/j.ccr.2014.02.004.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Biphenyl Compounds
  • GLI2 protein, human
  • Hedgehog Proteins
  • Kruppel-Like Transcription Factors
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • Nuclear Proteins
  • Oncogene Proteins
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Pyridines
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Repressor Proteins
  • SHH protein, human
  • SMO protein, human
  • SUFU protein, human
  • Smoothened Receptor
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Zinc Finger Protein Gli2
  • sonidegib
  • Proto-Oncogene Proteins c-akt
  • TERT protein, human
  • Telomerase
  • DDX3X protein, human
  • DEAD-box RNA Helicases

Associated data

  • GENBANK/GSE49243
  • GENBANK/GSE49377
  • GENBANK/GSE49576