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

Cancer Cell
Authors
Keywords
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.

Year of Publication
2014
Journal
Cancer Cell
Volume
25
Issue
3
Pages
393-405
Date Published
2014 Mar 17
ISSN
1878-3686
URL
DOI
10.1016/j.ccr.2014.02.004
PubMed ID
24651015
PubMed Central ID
PMC4493053
Links
Grant list
K08 NS075144 / NS / NINDS NIH HHS / United States