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Grant Details

Grant Number: 5R01CA230712-04 Interpret this number
Primary Investigator: Jenkins, Robert
Organization: Mayo Clinic Rochester
Project Title: (PQ3) Understanding the Interactions Between Germline and Somatic Alterations in the Pathogenesis of Gliomas
Fiscal Year: 2021


Abstract

Provocative Question 3: Summary/Abstract This proposal addresses Provocative Question #3, “Do genetic interactions between germline variants and somatic mutations contribute to differences in tumor evolution?” The new 2016 WHO Classification of Tumors of the Central Nervous System utilizes two somatic alterations to molecularly classify adult diffuse glioma: IDH mutation and 1p/19q codeletion. We and others have shown that TERT promoter mutation further classifies gliomas into molecular subtypes with distinct clinical characteristics. In addition, during the last five years much has been learned about the germline predisposition to gliomas: genome-wide association studies (GWAS) have revealed that 25 regions in 24 genes are associated with glioma development. Our group identified many of these associations and fine-mapped two of them (MYC/CCDC26 and TP53) and demonstrated that the MYC/CCDC26 variant (rs55705857) is associated with IDH-mutant gliomas. Indeed we found rs55705857 to have an odds ratio>6 for development of IDH-mutated glioma and lowers the age of onset by ~10 years. It is clear that the risk allele of rs55705857 interacts with somatic IDH-mutation to accelerate low-grade glioma development. We hypothesize that germline variants interact with somatic alterations to accelerate the development of IDH-mutant and IDH wild-type gliomas. Our published and preliminary data provide strong evidence in support of this hypothesis; but it must be explored further. While each of the known 25 regions has been evaluated with respect to risk of the 2016 WHO molecular subtypes, an unbiased GWAS has yet to be performed. Thus, Aim 1 will cost- effectively utilize previously-collected GWAS data to identify novel germline variants that are associated with the WHO subtypes in order to provide better patient risk assessment. Aim 2 will translate these findings into the clinic by integrating the germline and somatic alterations to determine associations with patient survival. Lastly, Aim 3 will use functional genomics to begin to understand the mechanisms by with rs55705857 and other variants accelerate IDH-mutant glioma.



Publications

Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma.
Authors: Tesileanu C.M.S. , van den Bent M.J. , Sanson M. , Wick W. , Brandes A.A. , Clement P.M. , Erridge S.C. , Vogelbaum M.A. , Nowak A.K. , Baurain J.F. , et al. .
Source: Neuro-oncology, 2021-09-01; 23(9), p. 1547-1559.
PMID: 33914057
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Glioma: interaction of acquired and germline genetics.
Authors: Eckel-Passow J.E. , Lachance D.H. , Jenkins R.B. .
Source: Aging, 2021-08-12; 13(15), p. 19085-19087.
EPub date: 2021-08-12.
PMID: 34385404
Related Citations

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.
Authors: Tesileanu C.M.S. , Vallentgoed W.R. , Sanson M. , Taal W. , Clement P.M. , Wick W. , Brandes A.A. , Baurain J.F. , Chinot O.L. , Wheeler H. , et al. .
Source: Acta neuropathologica, 2021 06; 141(6), p. 945-957.
EPub date: 2021-03-19.
PMID: 33740099
Related Citations

Functional analysis of low-grade glioma genetic variants predicts key target genes and transcription factors.
Authors: Manjunath M. , Yan J. , Youn Y. , Drucker K.L. , Kollmeyer T.M. , McKinney A.M. , Zazubovich V. , Zhang Y. , Costello J.F. , Eckel-Passow J. , et al. .
Source: Neuro-oncology, 2021-04-12; 23(4), p. 638-649.
PMID: 33130899
Related Citations

Searching for causal relationships of glioma: a phenome-wide Mendelian randomisation study.
Authors: Saunders C.N. , Cornish A.J. , Kinnersley B. , Law P.J. , Houlston R.S. , Collaborators .
Source: British journal of cancer, 2021 01; 124(2), p. 447-454.
EPub date: 2020-10-06.
PMID: 33020596
Related Citations

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.
Authors: Eckel-Passow J.E. , Drucker K.L. , Kollmeyer T.M. , Kosel M.L. , Decker P.A. , Molinaro A.M. , Rice T. , Praska C.E. , Clark L. , Caron A. , et al. .
Source: Neuro-oncology, 2020-11-26; 22(11), p. 1602-1613.
PMID: 32386320
Related Citations

Concomitant 1p/19q co-deletion and IDH1/2, ATRX, and TP53 mutations within a single clone of "dual-genotype" IDH-mutant infiltrating gliomas.
Authors: Zepeda-Mendoza C.J. , Vaubel R.A. , Zarei S. , Ida C.M. , Matthews M. , Acree S. , Raghunathan A. , Giannini C. , Jenkins R.B. .
Source: Acta neuropathologica, 2020 06; 139(6), p. 1105-1107.
EPub date: 2020-03-13.
PMID: 32170402
Related Citations

Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma.
Authors: Molinaro A.M. , Hervey-Jumper S. , Morshed R.A. , Young J. , Han S.J. , Chunduru P. , Zhang Y. , Phillips J.J. , Shai A. , Lafontaine M. , et al. .
Source: JAMA oncology, 2020-04-01; 6(4), p. 495-503.
PMID: 32027343
Related Citations

Genomic and Phenotypic Characterization of a Broad Panel of Patient-Derived Xenografts Reflects the Diversity of Glioblastoma.
Authors: Vaubel R.A. , Tian S. , Remonde D. , Schroeder M.A. , Mladek A.C. , Kitange G.J. , Caron A. , Kollmeyer T.M. , Grove R. , Peng S. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2020-03-01; 26(5), p. 1094-1104.
EPub date: 2019-12-18.
PMID: 31852831
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