The Causes of Glioma
A team of researchers have used multiple GWAS studies to identify 13 new genetic markers associated with glioma and to confirm another 13 markers discovered in previous investigations. The study, published in Nature Genetics, was also able to show clear differences in the genetic risk factors for high-grade Glioblastoma (GBM) and low-grade, non-GMB tumours.
Glioma accounts for 27% of all primary brain tumours and can largely be divided into cases of GBM tumours and cases of non-GBM tumours. GBM tumours are the most common form of the disease and typically have a poor prognosis regardless of medical care. Only 5% of GBM cases show a survival rate of more than five years. Previous studies have been unable to identify environmental factors that contribute to glioma, so there has been an increased push towards understanding the genomic roots of the disease.
This study, led by researchers at Baylor College of Medicine, used genomic data from one existing genome-wide association study (GWAS) and two new ones which collectively provided the genetic information of 30,686 people. Of the participants, 12,496 were cases (6,191 with GBM and 5,819 with non-GBM tumours) and 18,190 were controls, collected from eight studies of European descendants.
Examining the single nucleotide polymorphisms (SNPs) of the participants allowed the team to confirm that 13 previously-identified SNPs were related to GBM. In some cases, the SNPs changed classification (high risk, low risk, or without statistical significance). The team also identified 5 new loci linked to GBM and 8 new loci linked to non-GBM tumours.
“Until now our understanding of the risks of developing glioma has been limited,” said Melissa Bondy, Ph.D., lead. “In this work we confirmed 13 previously identified markers and uncovered 13 new genetic markers associated with this aggressive disease. We now have a more comprehensive genetic profile of the disease spectrum that expands our understanding of glioma susceptibility.”
This is thought to be the first study to directly examine the differences between genomic risk factors between GBM and non-GBM cases.
“Collectively, our findings provide strong evidence for specific associations for the different glioma subtypes, consistent with their previously described distinctive molecular profiles, presumably resulting from different etiological pathways,” the authors wrote. “Across the new and known risk loci, we found a significant enrichment of overlap with enhancers in H9-derived neuronal progenitor cells. These observations support the assertion that the loci identified in the GWAS influence glioma risk through effects on neural cis regulatory networks and that they are strongly involved in transcriptional initiation and enhancement.”
The team then used expression quantitative trait loci analysis to further examine the 13 new loci. Using RNA sequencing data from 103 people and blood eQTL data from 5,311 individuals, they identified a range of different signals associated with the risk loci, suggesting that each of the loci uses different mechanistic pathways to influence health.
Overall, the team estimated that the currently known risk SNPs only account for 27% of GMB risk loci and 37% of non-GBM risk loci.
“Therefore, further GWAS-based analyses in concert with functional analyses should lead to additional insights into the biology and etiological basis of the different glioma histologies,” the authors wrote. Building a greater understanding the genomic origins of glioma may be able to help us develop more effective treatment therapies in future and potentially, improve the mortality rate of the disease.