Adult diffuse glioma GWAS by molecular subtype identifies variants inD2HGDHandFAM20C

Abstract

Background Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. Methods A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10−8. Results Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10−10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10−8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10−9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10−10). Conclusions Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

Fam20C Overexpression Predicts Poor Outcomes and is a Diagnostic Biomarker in Lower-Grade Glioma

“…Adult diffuse glial tumor GWAS contains variants of D2HGDH and Fam20C in different molecular subtypes. In IDH mutant gliomas, the nine variants located on chromosome two of D2HGDH and those in its vicinity are all significant genome-wide ( Eckel-Passow et al, 2020 ).…”

The immunogenetics of viral antigen response is associated with sub-type specific glioma risk and survival

“…The second dataset (yellow) included 659 cases and 586 controls from the University of California, San Francisco (UCSF) Adult Glioma Study (AGS) genotyped on the Illumina HumanHap370duo panel 32 . The third set (blue) included 1973 cases from the Mayo Clinic and UCSF AGS and 1859 controls from the Glioma International Case-Control Study (GICC) who were genotyped on the Illumina OncoArray, as previously described 18,31–34 . The three resulting case-control datasets were processed through quality controls as described in the main text and imputed using the TOPMed imputation server.…”

“…We analyzed three glioma case-control sets assembled based on genotyping platform and study population for a total sample size of 3418 cases and 8156 controls (Figure 1, Table 1). The first set included 1973 cases from the Mayo Clinic and University of California, San Francisco (UCSF) Adult Glioma Study and 1859 controls from the Glioma International Case-Control Study (GICC) who were genotyped on the Illumina OncoArray, as previously described [33][34][35][36][37] . The second dataset included 659 cases and 586 controls from the UCSF Adult Glioma study genotyped on the Illumina HumanHap370duo panel 34 .…”

“…The identification of key somatic molecular alterations (e.g. IDH mutation, 1p/19q chromosomal arm codeletion, TERT mutation), which drastically affect glioma prognosis, have uncovered subtype-specific risk factors 17,18 . Recently, several studies/clinical trials have suggested a prognostic benefit of antiviral medications in the treatment of glioma 19–21 .…”

Glioma: interaction of acquired and germline genetics

“…Notably, these variants only reached genome-wide significance when the GWAS was performed within these two histological subtypes. More recently, our team performed a GWAS using the 2016 WHO criteria, stratifying patients by IDH mutation and 1p/19q codeletion and identified two additional novel regions: SNPs in D2HGDH were associated with tumors that had an IDH mutation and a SNP near FAM20C was associated with tumors that had both IDH mutation and 1p/19q codeletion [4]. The observed germline associations likely reflect the progression of glioma development.…”