Whole-genome sequencing of glioblastoma reveals enrichment of non-coding constraint mutations in known and novel genes.

Genome Biology
Sharadha SakthikumarKarin Forsberg-Nilsson

Abstract

Glioblastoma (GBM) has one of the worst 5-year survival rates of all cancers. While genomic studies of the disease have been performed, alterations in the non-coding regulatory regions of GBM have largely remained unexplored. We apply whole-genome sequencing (WGS) to identify non-coding mutations, with regulatory potential in GBM, under the hypothesis that regions of evolutionary constraint are likely to be functional, and somatic mutations are likely more damaging than in unconstrained regions. We validate our GBM cohort, finding similar copy number aberrations and mutated genes based on coding mutations as previous studies. Performing analysis on non-coding constraint mutations and their position relative to nearby genes, we find a significant enrichment of non-coding constraint mutations in the neighborhood of 78 genes that have previously been implicated in GBM. Among them, SEMA3C and DYNC1I1 show the highest frequencies of alterations, with multiple mutations overlapping transcription factor binding sites. We find that a non-coding constraint mutation in the SEMA3C promoter reduces the DNA binding capacity of the region. We also identify 1776 other genes enriched for non-coding constraint mutations with likely regulatory p...Continue Reading

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Citations

May 1, 2021·Microorganisms·Zihao YuanWenjin Jim Zheng
Jul 10, 2021·Trends in Genetics : TIG·Nicole A Leypold, Michael R Speicher

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Methods Mentioned

BETA
ChIP-seq
electrophoretic mobility shift assay
Assay
immunoprecipitation
Protein

Software Mentioned

Strelka
MuTSigCV
ENCODE
R Foundation for Statistical Computing
ORegAnno
UCSC genome browser
MuTect2
cBioPortal
ascatNGS
UCSC

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