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Molecular Cancer Research
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Cancer “-omics”

The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients

Ajay Chatrath, Manjari Kiran, Pankaj Kumar, Aakrosh Ratan and Anindya Dutta
Ajay Chatrath
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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Manjari Kiran
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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Pankaj Kumar
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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Aakrosh Ratan
2Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
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  • ORCID record for Aakrosh Ratan
Anindya Dutta
1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
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  • ORCID record for Anindya Dutta
  • For correspondence: ad8q@virginia.edu
DOI: 10.1158/1541-7786.MCR-18-0996 Published May 2019
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    Figure 1.

    A flowchart describing the steps involved in identifying prognostic germline variants.

  • Figure 2.
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    Figure 2.

    Prognostic germline variants in the TCGA dataset. A, Of the 4.4 million unique variants called in the TCGA dataset, we ran Cox regression on the 196,022 germline variants found in gnomAD with an allele frequency greater than 5% and found in 15 or more of the TCGA lower grade glioma patients. B–E, Similar to the 196,022 germline variants, the 271 prognostic variants are mostly found in protein-coding genes (B), are located in introns (C), and are single nucleotide polymorphisms (SNP; D). E, Most single-nucleotide polymorphisms cause transitions.

  • Figure 3.
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    Figure 3.

    rs61757955 is a highly prognostic germline variant identified in the TCGA dataset. A, Manhattan plot showing the P values resulting from testing each germline variant by Cox regression, controlling for the 11 variables in bolded in Table 1. Two variants passed the FDR threshold in the TCGA dataset. B, A Kaplan–Meier plot depicting the deleterious outcome associated with rs61757955, adjusting for the eleven covariates. C, ROC curve at 7 years. rs61757955 increases the area under the curve compared with the 11 covariates alone, suggesting that it improves the clinical model. D, Separation of patients on the basis of whether or not they have this germline variant to determine which genes are induced or repressed in patients with rs61757955. Subsequent gene set enrichment analysis reveals that patients with this germline variant exhibit upregulation of the genes involved with KRAS signaling.

  • Figure 4.
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    Figure 4.

    rs34988193 is a prognostic variant predicted to be highly deleterious. A, A Manhattan plot with the P values resulting from testing each germline variant by Cox regression, controlling for the 11 covariates in bolded in Table 1. rs34988193 is prognostic (FDR < 0.10) in the TCGA when restricting the analysis to the top 0.1% most deleterious variants by CADD. B and C, Kaplan–Meier plots depicting the deleterious outcome associated with rs34988193 in the TCGA (C) and CGGA datasets (D), adjusted for the 11 covariates. D, A schematic showing that this variant is located in the ninth ankyrin repeat of ANKDD1a. The predicted protein structure of ANKDD1a reveals that this variant leads to an amino acid change from lysine to glutamate on the loop of an ankyrin repeat. E, Multiple sequence alignment of ANKDD1a in 22 species showing that lysine is conserved at this position in all of the species with this protein. F, ROC curves comparing the ability of two survival models to label patients as alive or dead after 7 years of follow up. The inclusion of rs61757955 variant status, rs34988193 variant status, GRB2 expression, and ANKDD1a expression significantly improves the survival prediction compared with the 11 covariates bolded in Table 1 alone (P = 0.0279).

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  • Table 1.

    List of variables that are known to be associated with differences in survival in lower grade glioma patients

    CovariateMedian (min–max) or number of patients
    Age41 (14–87)
    GenderFemale250
    Male200
    Somatic mutation count50 (0–12255)
    Percent aneuploidy11% (5.2E-4%–95%)
    log(TERT Expression)1.0 (0.0–9.1) FPKM
    Principal component 1 (PC1)0.043 (−0.091–0.064)
    Principal component 2 (PC2)−0.017 (−0.23–0.17)
    Principal component 3 (PC3)−0.53 (1.34E-4–0.33)
    Histologic typeAstroctyoma172
    Oligoastrocytoma113
    Oligodendroglioma165
    Tumor locationFrontal lobe265
    Temporal lobe125
    Parietal lobe42
    Other18
    GradeG2212
    G3237
    Cannot be assessed1
    Treatment siteHenry Fords Hospital82
    Case Western St. Joseph Hospital90
    Other278
    IDH MutantWild type83
    Mutant367
    1p/19q CodeletionAbsent303
    Present147
    MGMT Promoter methylationUnmethylated80
    Methylated370
    Chr 7 gain/Chr 10 lossAbsent399
    Present51
    TP53 MutantAbsent232
    Present218
    • NOTE: Eleven variables (bolded) were selected by Lasso for inclusion in the survival model. We used these 11 variables as covariates in our Cox regression model when testing each germline variant.

  • Table 2.

    Description of the prognostic germline variants identified in this study

    Aa
    VariantChromPosRefAltPopulation frequencySample sizeNumber of heterozygotesNumber of homozygotesGene nameMedian expression (FPKM)PHR
    rs617579551775318086AG5.01%291210GRB242.27.08E-1020.4
    rs28672782111446622CT16.27%50155BRSK27.29<1E-161.15E-10
    Bb
    VariantChromPosRefAltPopulation frequencyCADD ScorePhyloP ScoreGene nameDatasetSample sizeNumber of heterozygotesNumber of homozygotesPHR
    rs349881931564943580AG30.90%328.42ANKDD1aTCGA450199520.001131.73
    CGGA761820.07431.79
    • ↵aA description of the two prognostic germline variants (FDR < 0.10) in the TCGA dataset identified when testing all 196,022 germline variants.

    • ↵bA description of the prognostic germline variant (FDR < 0.10) rs34988193 in ANKDD1a identified when the analysis was restricted to only germline variants with a combined annotation dependent depletion (CADD) score greater than 30 in the TCGA and CGGA datasets.

  • Table 3.

    The association between the germline variant rs61757955 and genomic and histological variables

    VariableMean or Percentage (Wild Type)Mean or Percentage (Mutant)P-value
    CIC Mutated15.9%38.1%0.017
    1p/19q Co-deletion25.2%47.6%0.038
    Oligodendroglioma33.7%42.9%0.475
    Total Somatic Mutation Count30.930.00.766
    Percent Aneuploidy15.1%11.7%0.524
    Astrocytoma38.1%42.9%0.651
    Grade 353.0%42.9%0.497
    IDH Mutated78.1%85.7%0.583
    1p/19q Co-deletion25.2%47.6%0.038
    MGMT Promoter Methylation77.8%81.0%1.000
    Chr 7 Gain/Chr 10 Loss13.0%9.5%1.000
    Expression of GRB2 (FPKM)45.744.40.636
    • NOTE: Patients were divided based on whether or not they had the germline variant rs61757955. Patients with the germline variant rs61757955 were more likely (p < 0.05) to have CIC-mutated gliomas and the 1p/19q codeletion (bold).

Additional Files

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    • All Supplementary Figures and Tables - S1. A boxplot representing the percentage of variants called in the whole exome sequenced (WXS) tumor sample that is likely somatic mutations. S2. Correlation between the variant allele frequencies calculated from the four variant sets and the distribution of allele frequencies. S3. Principal components calculated from germline variants from the whole exome sequencing data from the non-tumor samples. S4. Kaplan-Meier plot for the germline variant rs28672782 in BRSK2. Table S1. Quality control checks reveal that somatic mutations and RNA editing did not affect the results of our analysis. Table S2. Correlation between the allele frequencies calculated in our four variant sets and the allele frequencies reported by gnomAD. Table S3. Variants genetically linked to rs61757955 in the European population, the population that is most similar to the TCGA lower grade glioma patient population. Table S4. Results from testing for an association between the germline variant rs34988193 and genomic and histological variables.
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Molecular Cancer Research: 17 (5)
May 2019
Volume 17, Issue 5
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The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients
Ajay Chatrath, Manjari Kiran, Pankaj Kumar, Aakrosh Ratan and Anindya Dutta
Mol Cancer Res May 1 2019 (17) (5) 1075-1086; DOI: 10.1158/1541-7786.MCR-18-0996

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The Germline Variants rs61757955 and rs34988193 Are Predictive of Survival in Lower Grade Glioma Patients
Ajay Chatrath, Manjari Kiran, Pankaj Kumar, Aakrosh Ratan and Anindya Dutta
Mol Cancer Res May 1 2019 (17) (5) 1075-1086; DOI: 10.1158/1541-7786.MCR-18-0996
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