Abstract

Oligodendrogliomas are primary human brain tumors with a characteristic 1p/19q co-deletion of important prognostic relevance, but little is known about the pathology of this chromosomal mutation. We developed a network-based approach to identify novel cancer gene candidates in the region of the 1p/19q co-deletion. Gene regulatory networks were learned from gene expression and copy number data of 178 oligodendrogliomas and further used to quantify putative impacts of differentially expressed genes of the 1p/19q region on cancer-relevant pathways. We predicted 8 genes with strong impact on signaling pathways and 14 genes with strong impact on metabolic pathways widespread across the region of the 1p/19 co-deletion. Many of these candidates (e.g. ELTD1, SDHB, SEPW1, SLC17A7, SZRD1, THAP3, ZBTB17) are likely to push, whereas others (e.g. CAP1, HBXIP, KLK6, PARK7, PTAFR) might counteract oligodendroglioma development. For example, ELTD1, a functionally validated glioblastoma oncogene located on 1p, was overexpressed. Further, the known glioblastoma tumor suppressor SLC17A7 located on 19q was underexpressed. Moreover, known epigenetic alterations triggered by mutated SDHB in paragangliomas suggest that underexpressed SDHB in oligodendrogliomas may support and possibly enhance the epigenetic reprogramming induced by the IDH-mutation. We further analyzed rarely observed deletions and duplications of chromosomal arms within oligodendroglioma subcohorts identifying putative oncogenes and tumor suppressors that possibly influence the development of oligodendroglioma subgroups. Our in-depth computational study contributes to a better understanding of the pathology of the 1p/19q co-deletion and other chromosomal arm mutations. This might open opportunities for functional validations and new therapeutic strategies.

Highlights

  • Between 4 and 8 percent of all primary human brain tumors are classified as oligodendrogliomas [80]

  • Many under- and several overexpressed genes are observed within the region of the 1p/19q co-deletion We considered all oligodendrogliomas with 1p/19q codeletion and compared their gene expression profiles to normal brain references to identify differentially expressed genes

  • A knockdown of SDHB in mouse ovarian cancer cells enhanced cell proliferation and induced hypermethylation of histones promoting an epithelial-to-mesenchymal transition [2]. All these findings suggest that reduced expression of SDHB in oligodendrogliomas may support and possibly enhance the epigenetic reprogramming via the same pathomechanism induced by a heterozygous IDH-mutation that is found in each oligodendroglioma [13, 48]

Read more

Summary

Introduction

Between 4 and 8 percent of all primary human brain tumors are classified as oligodendrogliomas [80]. (G-CIMP) [53, 75] Both characteristic molecular markers (1p/19q co-deletion and IDH mutation) have recently been included into the new 2016 World Health Organization (WHO) classification system for tumors of the central nervous system [48]. This new classification utilizes histological features in combination with the co-occurrence of the 1p/19q co-deletion and the IDH-mutation to diagnose oligodendrogliomas. The search for inactivating point mutations on the remaining copies of the 1p and 19q arm identified FUBP1 located on 1p and CIC located on 19q as potential tumor suppressors [8, 20]. The recurrence of virtually identical 1p/19q co-deletions in different oligodendrogliomas does not allow to narrow down chromosomal regions on 1p and 19q where driver genes might be located

Methods
Results
Conclusion
Full Text
Paper version not known

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.