期刊
CANCER CELL
卷 25, 期 3, 页码 393-405出版社
CELL PRESS
DOI: 10.1016/j.ccr.2014.02.004
关键词
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资金
- PedBrain Tumor Project
- German Cancer Aid [109252]
- German Federal Ministry of Education and Research (Bundesministerium fur Bildung und Forschung) [01KU1201A, MedSys 0315416C, NGFNplus 01GS0883]
- Dutch Cancer Foundations KWF [2010-4713]
- KIKA
- Brain Tumor Charity
- Roche
- Novartis
- The Brain Tumour Charity [10/140] Funding Source: researchfish
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 gernnline, 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.
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