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. 2019 Mar 18;21(4):451-461.
doi: 10.1093/neuonc/noz009.

Using germline variants to estimate glioma and subtype risks

Jeanette E Eckel-Passow  1 , Paul A Decker  1 , Matt L Kosel  1 , Thomas M Kollmeyer  2 , Annette M Molinaro  3   4 , Terri Rice  3 , Alissa A Caron  2 , Kristen L Drucker  2 , Corinne E Praska  2 , Melike Pekmezci  5 , Helen M Hansen  3 , Lucie S McCoy  3 , Paige M Bracci  4 , Bradley J Erickson  6 , Claudia F Lucchinetti  7 , Joseph L Wiemels  8 , John K Wiencke  3   4   9 , Melissa L Bondy  10 , Beatrice Melin  11 , Terry C Burns  12 , Caterina Giannini  2 , Daniel H Lachance  2   7 , Margaret R Wrensch  3   4   9 , Robert B Jenkins  2
Affiliations

Using germline variants to estimate glioma and subtype risks

Jeanette E Eckel-Passow et al. Neuro Oncol. .

Abstract

Background: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes.

Methods: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray.

Results: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85.

Conclusions: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.

Keywords: classification; genotype; glioblastoma; glioma; polygenic.

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Figures

Fig. 1
Fig. 1
Estimated glioma risk score from the multinomial logistic regression model that molecularly classified patients: estimated risk scores of being (A) IDH wild-type, (B) IDH mutant 1p/19q non-codeleted, and (C) IDH mutant 1p/19q codeleted. The model was developed using Mayo Clinic glioma cases and controls and validated using UCSF glioma cases and controls.
Fig. 2
Fig. 2
Association between glioma risk score and relative risk of a specific glioma subtype, estimated from Mayo Clinic glioma cases and controls, for: (A) IDH wild-type, (B) IDH mutant 1p/19q non-codeleted, and (C) IDH mutant 1p/19q codeleted. Associations were validated using UCSF cases and controls for (D) IDH wild-type, (E) IDH mutant 1p/19q non-codeleted, and (F) IDH mutant 1p/19q codeleted. Odds ratios were calculated for percentiles of risk score relative to the middle category (45–55%) of risk scores.
Fig. 3
Fig. 3
Estimated probability of being IDH mutant from a logistic regression model that predicted IDH mutation status. Model was developed using Mayo Clinic glioma cases and validated using UCSF glioma cases.
See this image and copyright information in PMC

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