Deep sequencing of WNT-activated medulloblastomas reveals secondary SHH pathway activation

Excerpt

Initially described in 2011, it is now recognized that medulloblastomas (MB) can be stratified into four distinct molecular subgroups (WNT-activated, SHH-activated, Group 3, and Group 4) on the basis of underlying genetic alterations, transcriptional profiles, or genome-wide DNA methylation patterns that more accurately predict clinical outcomes than histologic features alone [4, 7]. The recurrent genetic alterations that characterize each of these four molecular subgroups have been described over the last few years [2, 5, 6, 8, 9]. WNT-activated MB, associated with favorable prognosis, are genetically defined by activating mutations in CTNNB1 (encoding beta-catenin) often accompanied by monosomy 6 and alterations in chromatin regulatory genes. SHH-activated MB, associated with intermediate or poor prognosis depending on the status of the TP53 tumor suppressor gene, are genetically characterized by alterations in components of the sonic hedgehog (SHH) signaling pathway including PTCH1, SMO, SUFU, and GLI2. Group 3 and Group 4 MB, associated with intermediate-to-poor prognosis, are characterized by activation of MYC or MYCN transcriptional networks often due to amplification or structural rearrangement involving these genes. Recent studies have suggested that there is heterogeneity within these four molecular subgroups, now with 12 distinct subtypes that can be separated by DNA methylation profiling and are each associated with distinct genetic alterations [1, 6]. Additional studies have shown that many of the underlying genetic alterations in MB may only be present in spatially restricted subclones within the tumor [5]. However, in all patients studied to date, the molecular subgroup has been constant in all regions of the primary tumor, as well as at time of recurrence or metastasis, suggesting that the molecular subgroup is defined at the time of tumor initiation and is not affected by clonal genetic evolution, therapy, or other factors [5]. In addition, all MB studied to date have been classified into one of the four primary molecular subgroups that are thought to be mutually exclusive, and switching between these subgroups or tumors with dual activation of two or more of the signaling pathways that define the four primary molecular subgroups have not been reported. Herein, we report the results of deep sequencing on a cohort of WNT-activated MB and show that they often acquire subclonal genetic alterations that secondarily activate the SHH pathway, a finding that may have important prognostic and therapeutic significance. …