Decoding Somatic Driver Gene Mutations and Affected Signaling Pathways in Human Medulloblastoma Subgroups

Abstract

Medulloblastoma is the most common malignant pediatric brain tumor. Prior studies have concentrated their efforts studying the four molecular subgroups: SHH, Wnt, group 3, and group 4. SHH and Wnt are driven by their canonical pathways. Groups 3 and 4 are highly metastatic and associated with aberrations in epigenetic regulators. Recent developments in the field have revealed that these subgroups are not as homogenous as previously believed. The objective of this study is to investigate the involvement of somatic driver gene mutations in these medulloblastoma subgroups. We obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied in a large cohort. We identified somatic driver gene mutations and the signaling pathways affected by these driver genes for medulloblastoma subgroups using bioinformatics tools. We have revealed novel infrequent drivers in these subgroups that contribute to our understanding of tumor heterogeneity in medulloblastoma. Normally SHH signaling is activated in the SHH subgroup, however, we determined gain-of-function mutations in ubiquitin ligase (CUL1) that inhibit Gli-mediated transcription. This suggests a potential hindrance in SHH signaling for some patients. For group 3, gain-of-function in the inhibitor of proinflammatory cytokines (HIVEP3) suggests an immunosuppressive phenotype and thus a more hostile tumor microenvironment. Surprisingly, group 4 tumors possess mutations that may prompt the activation of Wnt signaling through gain-of-function mutations in MUC16 and PCDH9. These infrequent mutations detected in this study could be due to subclonal or spatially restricted alterations. The investigation of aberrant driver gene mutations can lead to the identification of new drug targets and a greater understanding of human medulloblastoma heterogeneity.

Protocadherins at the Crossroad of Signaling Pathways

“…Neuronal apoptosis is induced by ncPcdh overexpression or cPcdh loss. In oncogenesis, most Pcdhs seem to have a tumor suppressor function, as for several cancer types their downregulation [with the exception of PCDHB9 (Mukai et al, 2017;Sekino et al, 2019), and PCDH9 (Robbins et al, 2018)] correlates with tumor survival. Taken together, the precise dosage control of Pcdhs might therefore be crucial for cell survival in different contexts.…”

Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan

“…Detection of somatic mutation in cancers by using RNA-Seq data has the benefit of having no additional cost after the initial sequencing [18,19]. Using limited resource, we applied RNA-Seq variant calling to detect somatic mutations in our cohort series.…”

“…Moreover, therapeutic targets may be deciphered from the identified mutations [15]. Pugh et al [18] and Robbins et al [19] uncovered subgroup-specific somatic mutations and the affected pathways of MB through exome sequencing. We attempted to explore potential somatic and germline mutations relating to therapeutic targets.…”

Characterization of Epigenetic and Transcriptional Landscape in Infantile Hemangiomas with ATAC-Seq and RNA-Seq

“…MMPs are involved in angiogenesis during tumor metastasis and invasion [39]. HIVEP3 plays a critical role in female-biased autoimmune disorders and may make the tumor more progressive by changing the immune environment [40,41].…”