Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.
GWAS glioma
allergy
glioblastoma
molecular subtype
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
26 11 2020
26 11 2020
Historique:
pubmed:
10
5
2020
medline:
17
3
2021
entrez:
10
5
2020
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 32386320
pii: 5835318
doi: 10.1093/neuonc/noaa117
pmc: PMC7690366
doi:
Substances chimiques
Extracellular Matrix Proteins
0
Alcohol Oxidoreductases
EC 1.1.-
Isocitrate Dehydrogenase
EC 1.1.1.41
D2HGDH protein, human
EC 1.1.99.2
Casein Kinase I
EC 2.7.11.1
FAM20C protein, human
EC 2.7.11.1
Telomerase
EC 2.7.7.49
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1602-1613Subventions
Organisme : NCI NIH HHS
ID : R01 CA139020
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800032C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800009C
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA108961
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230712
Pays : United States
Organisme : NCI NIH HHS
ID : R25 CA112355
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800015I
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA126831
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097257
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800032I
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800015C
Pays : United States
Organisme : NCCDPHP CDC HHS
ID : NU58DP006344
Pays : United States
Organisme : NINDS NIH HHS
ID : RC1 NS068222
Pays : United States
Organisme : NCRR NIH HHS
ID : UL1 RR024131
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA082103
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA207360
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA163687
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA052689
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261201800009I
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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