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      Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

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      Cancer Cell
      Elsevier BV

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          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. Copyright © 2014 Elsevier Inc. All rights reserved.

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          Author and article information

          Journal
          Cancer Cell
          Cancer Cell
          Elsevier BV
          15356108
          March 2014
          March 2014
          : 25
          : 3
          : 393-405
          Article
          10.1016/j.ccr.2014.02.004
          24651015
          4a432dfb-65e9-494d-84aa-e018f1f56fe2
          © 2014

          https://www.elsevier.com/tdm/userlicense/1.0/

          https://www.elsevier.com/open-access/userlicense/1.0/

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