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

Abstract

Summary 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.

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

“…A more direct role of Hh pathway has been established in the pathogenesis of medulloblastoma characterized by the presence of mutations in central components of Hh signaling (Kool et al , 2014); therefore, we tested whether the Fbxl17–Sufu axis operates in medulloblastoma cancer cells. DAOY human medulloblastoma cells have been reported to be responsive to Hh signaling modulation (Gotschel et al , 2013).…”

“…Mutations in the components of Hh signaling are a feature of SHH medulloblastoma (Kool et al , 2014). We show that in a case of familial medulloblastoma, altered proteolysis of Sufu plays an active role in the induction of sustained Hh signaling.…”

“…We show that in a case of familial medulloblastoma, altered proteolysis of Sufu plays an active role in the induction of sustained Hh signaling. Importantly, mutations in other components of Hh signaling pathway, such as Ptch (present in > 50% of SHH medulloblastoma) (Kool et al , 2014), will also affect Sufu protein levels, given the effect of pathway activation on Sufu protein mediated by Fbxl17. Thus, in the majority of SHH medulloblastoma, Sufu protein levels will be low due to the constitutive activation of Hh signaling.…”

“…Importantly, heterozygous loss of Sufu, in conjunction with the loss of p53, leads to the development of medulloblastoma and rhabdomyosarcoma (Lee et al , 2007). Germline Sufu mutations have been identified in medulloblastoma (Taylor et al , 2002; Kool et al , 2014) and associated with the development of medulloblastoma in Gorlin syndrome (Pastorino et al , 2009; Kijima et al , 2012; Smith et al , 2014). Furthermore, somatic Sufu mutations have been identified in multiple other malignancies, including prostate cancer (Sheng et al , 2004).…”

WHO’s arrived in 2016! An updated weather forecast for integrated brain tumor diagnosis

“…Molecular variants now include WNT-activated; SHH-activated and TP53-wildtype; SHH-activated and TP53-mutant; and non-WNT/non-SHH, with the subdivision of the SHH-activated variant reflecting the recognition that those with TP53 mutation and/or strong widespread p53 positivity have a particularly dismal prognosis [3,12,18]. In addition, these tumors differ from their TP53-wildtype counterparts by presenting mostly between the ages of 3 and 17 years, often showing anaplastic features, being resistant to current therapies (including SMO inhibitors), and commonly arising in patients with germline TP53 mutations (i.e., Li-Fraumeni syndrome), thus necessitating both genetic counseling for the family and novel patient management strategies [5,12]. The less specific non-WNT/non-SHH category is, unfortunately, the largest, but reflects the technical difficulties in reliably distinguishing molecular groups 3 and 4; nevertheless, those with genomic or epigenomic techniques capable of making this distinction can opt to utilize these designations instead.…”