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Brain Cancer GWAS Uncovers 13 New Genetic Markers Associated With Glioma

NEW YORK (GenomeWeb) – A GWAS study of glioma has uncovered 13 new genetic markers associated with the disease, and confirmed 13 previously discovered markers. The researchers also found a clear difference in the genetic risk factors for high-grade glioblastoma versus low-grade glioma.

In a paper published today in Nature Genetics, Baylor College of Medicine researcher and senior author Melissa Bondy and an international team of colleagues analyzed GWAS SNP data that passed quality control for 12,496 cases — 6,191 of which were classified as glioblastomas and 5,819 classified as non-glioblastoma tumors — and 18,190 controls from eight studies of individuals of European ancestry.

The combined meta-analysis confirmed 13 previously identified risk SNPs in TP53, TERT, EGFR, CDKN2B–AS1, RTEL1, CCDC26, PHLDB1, TERC, POLR3B, and ETFA — some of which showed even greater evidence for association with the disease, some of which retained genome-wide significance, and some of which did not retain statistical significance.

Further, the team uncovered new risk loci for glioblastoma at 1p31.3, 11q14.1, 16p13.3, 16q12.1, and 22q13.1; and for non-glioblastoma tumors at 1q32.1, 1q44, 2q33.3, 3p14.1, 10q24.33, 11q21, 14q12, and 16p13.3.

"Until now our understanding of the risks of developing glioma has been limited," Bondy said in a statement. "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."

Importantly, the researchers emphasized, this study is the first to identify different genetic risk factor profiles for high-grade glioblastoma compared to low-grade glioma.

"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."

To further examine the 13 new risk loci, the researchers performed an expression quantitative trait loci analysis using RNA-sequencing data on ten regions of normal human brain from up to 103 individuals from the Genotype-Tissue Expression Project and blood eQTL data on 5,311 individuals from a previous study.

They found various signals associated with the different risk loci that suggest different mechanisms pathways involved in tumor formation and survival. At the 16q12.1 loci, for example, they found that the glioblastoma association signal was also significantly associated with HEATR3 expression in nine of 10 regions of the brain. "The observation that variation at 16q12.1 is associated with risk of testicular and esophageal cancer suggests that the locus has pleiotropic effects on tumor risk," the researchers noted. "Similarly, significant associations between gene expression and glioma risk were observed at the glioblastoma loci 1p31.3 (JAK1, brain cortex and cerebellar hemisphere), 16p13.3 (POLR3K, whole blood), and 22q13.1 (CTA-228A9.3, brain cerebellum; PICK1, brain hippocampus)."

They concluded that currently identified risk SNPs for glioma account for only about 27 percent and 37 percent of the familial risk of glioblastoma and non-glioblastoma tumors, respectively. "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," which could lead to the development of new therapies for these tumors, the authors added.