Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors

Abstract

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10−9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10−10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10−8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10−11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10−10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10−9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10−10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10−10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10−9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10−8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10−10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10−11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10−9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Genome-Wide Association Studies in Glioma

“…The largest and most recent glioma GWAS was carried out in 2017 by Melin and colleagues (24). This featured a meta-analysis of six existing GWAS and two new GWAS making use of the Illumina OncoArray (35), in total comprising 12,496 cases and 18,190 controls.…”

“…At the GBM locus 1p31.3, the risk allele of rs12752552 ( T ) is associated with increased expression of JAK1 in brain cortex and cerebellar hemisphere (24). JAK1 is involved in actomyosin contractility in tumor cells and stroma (36), and dysregulation of JAK–STAT signaling is thought to play an important role in development of high-grade glioma (37), providing an attractive mechanistic basis for the 1p31.3 association.…”

“…The non-GBM risk SNP rs4252707 is within the eighth intron of MDM4 , with the risk allele ( A ) associated with increased expression of this gene (24). MDM4 is amplified in glioma tumors lacking TP53 mutation, consistent with its role in inactivation of p53-dependent growth control (38).…”

“…The strongest association with telomere length at 3q26.2 was exhibited by rs10936599, which is also a known colorectal cancer risk locus (53, 54); there is moderate correlation between rs10936599 and rs1920116 ( r 2 = 0.44, D′ = 0.72) suggesting these are not independent signals. In the latest glioma GWAS, the 3q26.2 locus does not attain genome-wide significance (24). …”

“…The combination of technological advancements and collaborative efforts in establishment of consortia such as the Glioma International Case–Control (GICC) study (22) has enabled genotyping of hundreds of thousands of variants in thousands of glioma cases and controls. It is now recognized that a substantial component of glioma genetic risk is explained by combinations of common polymorphisms of modest effect (23), with 27 loci in total identified so far from glioma GWAS (24–33). …”