Whole exome sequencing–based analysis to identify DNA damage repair deficiency as a major contributor to gliomagenesis in adult diffuse gliomas

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  • 1 Departments of Biostatistics and Medical Informatics,
  • 6 Medical Biology,
  • 7 Pathology, and
  • 9 Neurosurgery, Acibadem Mehmet Ali Aydınlar University, School of Medicine, Istanbul;
  • 2 Department of Medical Engineering, Acibadem Mehmet Ali Aydınlar University, School of Engineering, Istanbul, Turkey;
  • 3 Department of Genetics, Yale Center for Genome Analysis, Yale University, School of Medicine, New Haven, Connecticut;
  • 4 Izmir International Biomedicine and Genome Institute (IBG), Dokuz Eylül University, Izmir;
  • 5 Department of Medical Biology, Dokuz Eylül University, Izmir; and
  • 8 Department of Molecular Biology, Acibadem Mehmet Ali Aydınlar University, School of Arts and Sciences, Istanbul, Turkey


Processes that cause or contribute to cancer, such as aging, exposure to carcinogens, or DNA damage repair deficiency (DDRd), create predictable and traceable nucleotide alterations in one’s genetic code (termed “mutational signatures”). Large studies have previously identified various such mutational signatures across cancers that can be attributed to the specific causative processes. To gain further insight into the processes in glioma development, the authors analyzed mutational signatures in adult diffuse gliomas (DGs).


Twenty-five DGs and paired blood samples were whole exome sequenced. Somatic mutational signatures were identified using 2 different methods. Associations of the signatures with age at diagnosis, molecular subset, and mutational load were investigated. As DDRd-related signatures were frequently observed, germline and somatic DDR gene mutations as well as microsatellite instability (MSI) status were determined for all samples. For validation of signature prevalence, publicly available data from The Cancer Genome Atlas (TCGA) were used.


Each tumor had a unique combination of signatures. The most common signatures were signature 1 (88%, aging related), signature 3 (52%, homologous recombination related), and signature 15 (56%, mismatch repair related). Eighty-four percent of the tumors contained at least 1 DDRd signature. The findings were validated using public TCGA data. The weight of signature 1 positively correlated with age (r = 0.43) while cumulative weight of DDRd signatures negatively correlated with age (r = −0.16). Each subject had at least 1 germline/somatic alteration in a DDR gene, the most common being the risk single nucleotide polymorphism rs1800734 in MLH1. The rs1800734-AA genotype had a higher cumulative DDRd weight as well as higher mutational load; TP53 was the most common somatically altered DDR gene. MSI was observed in 24% of the tumors. No significant associations of MSI status with mutational load, rs1800734, or the cumulative weight of DDRd signatures were identified.


Current findings suggest that DDRd may act as a fundamental mechanism in gliomagenesis rather than being a random, secondary event.

ABBREVIATIONS DDR = DNA damage repair; DDRd = DDR deficiency; DG = diffuse glioma; GBM = glioblastoma; INDEL = insertion-deletion; LGG = low-grade glioma; MMR = mismatch repair; MSI = microsatellite instability; MSI-H = tumor highly likely to harbor MSI; SNP = single nucleotide polymorphism; SNV = single nucleotide variant; TCGA = The Cancer Genome Atlas; Ti/Tv = transition/transversion; WES = whole exome sequencing.

Supplementary Materials

    • Supplementary Figure S1 & Tables S1–S3 (PDF 866 KB)

Contributor Notes

Correspondence Koray Ozduman: Acıbadem Mehmet Ali Aydınlar University, School of Medicine, Istanbul, Turkey. koray.ozduman@icloud.com.

INCLUDE WHEN CITING Published online April 5, 2019; DOI: 10.3171/2019.1.JNS182938.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.


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