title: Tumor-specific mutations in low-frequency genes affect their functional properties.
abstract: Causal genetic changes in oligodendrogliomas (OD) with 1p/19q co-deletion include mutations in IDH1, IDH2, CIC, FUBP1, TERT promoter and NOTCH1. However, it is generally assumed that more somatic mutations are required for tumorigenesis. This study aimed to establish whether genes mutated at low frequency can be involved in OD initiation and/or progression. We performed whole-genome sequencing on three anaplastic ODs with 1p/19q co-deletion. To estimate mutation frequency, we performed targeted resequencing on an additional 39 ODs. Whole-genome sequencing identified a total of 55 coding mutations (range 8-32 mutations per tumor), including known abnormalities in IDH1, IDH2, CIC and FUBP1. We also identified mutations in genes, most of which were previously not implicated in ODs. Targeted resequencing on 39 additional ODs confirmed that these genes are mutated at low frequency. Most of the mutations identified were predicted to have a deleterious functional effect. Functional analysis on a subset of these genes (e.g. NTN4 and MAGEH1) showed that the mutation affects the subcellular localization of the protein (n = 2/12). In addition, HOG cells stably expressing mutant GDI1 or XPO7 showed altered cell proliferation compared to those expressing wildtype constructs. Similarly, HOG cells expressing mutant SASH3 or GDI1 showed altered migration. The significantly higher rate of predicted deleterious mutations, the changes in subcellular localization and the effects on proliferation and/or migration indicate that many of these genes functionally may contribute to gliomagenesis and/or progression. These low-frequency genes and their affected pathways may provide new treatment targets for this tumor type.
authors.affiliation: Department of Neurology, Be 430A, Erasmus Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Lale
authors.initials: L
authors.lastname: Erdem-Eraslan
authors.forename: Daphne
authors.initials: D
authors.lastname: Heijsman
authors.forename: Maurice
authors.initials: M
authors.lastname: de Wit
authors.forename: Andreas
authors.initials: A
authors.lastname: Kremer
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacchetti
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.forename: Peter A E
authors.initials: PA
authors.lastname: Sillevis Smitt
authors.forename: Pim J
authors.initials: PJ
authors.lastname: French
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055106:Genome-Wide Association Study; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D028884:Karyopherins / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014162:Transfection; D000097606:Exportin 1 Protein
chemical_list: D049452:Green Fluorescent Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D028884:Karyopherins; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D000097606:Exportin 1 Protein; C086796:GDP dissociation inhibitor 1; C115048:ZBTB18 protein, human; C485184:enhanced green fluorescent protein