Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: Evidence for distinct pathways of gliomagenesis

Kyle M. Walsh; Terri Rice; Paul A. Decker; Matthew L. Kosel; Thomas Kollmeyer; Helen M. Hansen; Shichun Zheng; Lucie S. McCoy; Paige M. Bracci; Erik Anderson; George Hsuang; Joe L. Wiemels; Alexander R. Pico; Ivan Smirnov; Annette M. Molinaro; Tarik Tihan; Mitchell S. Berger; Susan M. Chang; Michael D. Prados; Daniel H. Lachance; Hugues Sicotte; Jeanette E. Eckel-Passow; John K. Wiencke; Robert B. Jenkins; Margaret R. Wrensch

doi:10.1093/neuonc/not051

Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: Evidence for distinct pathways of gliomagenesis

Kyle M. Walsh, Terri Rice, Paul A. Decker, Matthew L. Kosel, Thomas Kollmeyer, Helen M. Hansen, Shichun Zheng, Lucie S. McCoy, Paige M. Bracci, Erik Anderson, George Hsuang, Joe L. Wiemels, Alexander R. Pico, Ivan Smirnov, Annette M. Molinaro, Tarik Tihan, Mitchell S. Berger, Susan M. Chang, Michael D. Prados, Daniel H. LachanceHugues Sicotte, Jeanette E. Eckel-Passow, John K. Wiencke, Robert B. Jenkins, Margaret R. Wrensch

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Abstract

BackgroundGenome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.MethodsSNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate.ResultsFour SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10^-22 and P = 9.5 × 10^-7, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10^-4 and P = 2.5 × 10^-4, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.ConclusionsCarrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).

Original language	English (US)
Pages (from-to)	1041-1047
Number of pages	7
Journal	Neuro-oncology
Volume	15
Issue number	8
DOIs	https://doi.org/10.1093/neuonc/not051
State	Published - Aug 2013

Keywords

age at diagnosis
glioma
single nucleotide polymorphism
telomerase
telomere

ASJC Scopus subject areas

Oncology
Clinical Neurology
Cancer Research

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10.1093/neuonc/not051

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Walsh, K. M., Rice, T., Decker, P. A., Kosel, M. L., Kollmeyer, T., Hansen, H. M., Zheng, S., McCoy, L. S., Bracci, P. M., Anderson, E., Hsuang, G., Wiemels, J. L., Pico, A. R., Smirnov, I., Molinaro, A. M., Tihan, T., Berger, M. S., Chang, S. M., Prados, M. D., ... Wrensch, M. R. (2013). Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: Evidence for distinct pathways of gliomagenesis. Neuro-oncology, 15(8), 1041-1047. https://doi.org/10.1093/neuonc/not051

Walsh, KM, Rice, T, Decker, PA, Kosel, ML, Kollmeyer, T, Hansen, HM, Zheng, S, McCoy, LS, Bracci, PM, Anderson, E, Hsuang, G, Wiemels, JL, Pico, AR, Smirnov, I, Molinaro, AM, Tihan, T, Berger, MS, Chang, SM, Prados, MD, Lachance, DH, Sicotte, H, Eckel-Passow, JE, Wiencke, JK, Jenkins, RB & Wrensch, MR 2013, 'Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: Evidence for distinct pathways of gliomagenesis', Neuro-oncology, vol. 15, no. 8, pp. 1041-1047. https://doi.org/10.1093/neuonc/not051

@article{ea1462fb7d3e4f24a3a6061948b42a33,

title = "Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: Evidence for distinct pathways of gliomagenesis",

abstract = "BackgroundGenome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.MethodsSNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between {"}number of risk alleles{"} and {"}age at diagnosis,{"} adjusted for sex and study site and stratified by tumor grade/histology where appropriate.ResultsFour SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10-22 and P = 9.5 × 10-7, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10-4 and P = 2.5 × 10-4, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.ConclusionsCarrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).",

keywords = "age at diagnosis, glioma, single nucleotide polymorphism, telomerase, telomere",

author = "Walsh, {Kyle M.} and Terri Rice and Decker, {Paul A.} and Kosel, {Matthew L.} and Thomas Kollmeyer and Hansen, {Helen M.} and Shichun Zheng and McCoy, {Lucie S.} and Bracci, {Paige M.} and Erik Anderson and George Hsuang and Wiemels, {Joe L.} and Pico, {Alexander R.} and Ivan Smirnov and Molinaro, {Annette M.} and Tarik Tihan and Berger, {Mitchell S.} and Chang, {Susan M.} and Prados, {Michael D.} and Lachance, {Daniel H.} and Hugues Sicotte and Eckel-Passow, {Jeanette E.} and Wiencke, {John K.} and Jenkins, {Robert B.} and Wrensch, {Margaret R.}",

year = "2013",

month = aug,

doi = "10.1093/neuonc/not051",

language = "English (US)",

volume = "15",

pages = "1041--1047",

journal = "Neuro-oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "8",

}

TY - JOUR

T1 - Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients

T2 - Evidence for distinct pathways of gliomagenesis

AU - Walsh, Kyle M.

AU - Rice, Terri

AU - Decker, Paul A.

AU - Kosel, Matthew L.

AU - Kollmeyer, Thomas

AU - Hansen, Helen M.

AU - Zheng, Shichun

AU - McCoy, Lucie S.

AU - Bracci, Paige M.

AU - Anderson, Erik

AU - Hsuang, George

AU - Wiemels, Joe L.

AU - Pico, Alexander R.

AU - Smirnov, Ivan

AU - Molinaro, Annette M.

AU - Tihan, Tarik

AU - Berger, Mitchell S.

AU - Chang, Susan M.

AU - Prados, Michael D.

AU - Lachance, Daniel H.

AU - Sicotte, Hugues

AU - Eckel-Passow, Jeanette E.

AU - Wiencke, John K.

AU - Jenkins, Robert B.

AU - Wrensch, Margaret R.

PY - 2013/8

Y1 - 2013/8

N2 - BackgroundGenome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.MethodsSNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate.ResultsFour SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10-22 and P = 9.5 × 10-7, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10-4 and P = 2.5 × 10-4, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.ConclusionsCarrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).

AB - BackgroundGenome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma.MethodsSNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate.ResultsFour SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 × 10-22 and P = 9.5 × 10-7, respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 × 10-4 and P = 2.5 × 10-4, respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups.ConclusionsCarrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres).

KW - age at diagnosis

KW - glioma

KW - single nucleotide polymorphism

KW - telomerase

KW - telomere

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Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: Evidence for distinct pathways of gliomagenesis

Abstract

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