Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

ENGAGE Consortium Telomere Group

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82 × 10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48 × 10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83 × 10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

Original languageEnglish (US)
Pages (from-to)42468-42477
Number of pages10
JournalOncotarget
Volume6
Issue number40
DOIs
StatePublished - 2015

Fingerprint

Telomere
Glioma
Leukocytes
Single Nucleotide Polymorphism
Gene Components
Atlases
Telomerase
Random Allocation
Carcinogenesis
Genotype
Maintenance
Genome

Keywords

  • CST complex
  • Glioma
  • Single nucleotide polymorphism
  • Telomerase
  • Telomere

ASJC Scopus subject areas

  • Oncology

Cite this

Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk. / ENGAGE Consortium Telomere Group.

In: Oncotarget, Vol. 6, No. 40, 2015, p. 42468-42477.

Research output: Contribution to journalArticle

ENGAGE Consortium Telomere Group. / Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk. In: Oncotarget. 2015 ; Vol. 6, No. 40. pp. 42468-42477.
@article{377fa3d895204c1299b90f70cfb704b1,
title = "Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk",
abstract = "Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7{\%}) longer in glioma patients than controls in discovery analyses (P = 7.82 × 10-8) and 27bp (5.0{\%}) longer in glioma patients than controls in replication analyses (1.48 × 10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83 × 10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95{\%} C.I.=1.03-1.28) and TERT (O.R.=1.39; 95{\%} C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95{\%} C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95{\%} C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.",
keywords = "CST complex, Glioma, Single nucleotide polymorphism, Telomerase, Telomere",
author = "{ENGAGE Consortium Telomere Group} and Walsh, {Kyle M.} and Veryan Codd and Terri Rice and Nelson, {Christopher P.} and Smirnov, {Ivan V.} and McCoy, {Lucie S.} and Hansen, {Helen M.} and Edward Elhauge and Juhi Ojha and Francis, {Stephen S.} and Madsen, {Nils R.} and Bracci, {Paige M.} and Pico, {Alexander R.} and Molinaro, {Annette M.} and Tarik Tihan and Berger, {Mitchel S.} and Chang, {Susan M.} and Prados, {Michael D.} and Jenkins, {Robert Brian} and Wiemels, {Joseph L.} and Samani, {Nilesh J.} and Wiencke, {John K.} and Wrensch, {Margaret R.}",
year = "2015",
doi = "10.18632/oncotarget.6468",
language = "English (US)",
volume = "6",
pages = "42468--42477",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "40",

}

TY - JOUR

T1 - Longer genotypically-estimated leukocyte telomere length is associated with increased adult glioma risk

AU - ENGAGE Consortium Telomere Group

AU - Walsh, Kyle M.

AU - Codd, Veryan

AU - Rice, Terri

AU - Nelson, Christopher P.

AU - Smirnov, Ivan V.

AU - McCoy, Lucie S.

AU - Hansen, Helen M.

AU - Elhauge, Edward

AU - Ojha, Juhi

AU - Francis, Stephen S.

AU - Madsen, Nils R.

AU - Bracci, Paige M.

AU - Pico, Alexander R.

AU - Molinaro, Annette M.

AU - Tihan, Tarik

AU - Berger, Mitchel S.

AU - Chang, Susan M.

AU - Prados, Michael D.

AU - Jenkins, Robert Brian

AU - Wiemels, Joseph L.

AU - Samani, Nilesh J.

AU - Wiencke, John K.

AU - Wrensch, Margaret R.

PY - 2015

Y1 - 2015

N2 - Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82 × 10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48 × 10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83 × 10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

AB - Telomere maintenance has emerged as an important molecular feature with impacts on adult glioma susceptibility and prognosis. Whether longer or shorter leukocyte telomere length (LTL) is associated with glioma risk remains elusive and is often confounded by the effects of age and patient treatment. We sought to determine if genotypically-estimated LTL is associated with glioma risk and if inherited single nucleotide polymorphisms (SNPs) that are associated with LTL are glioma risk factors. Using a Mendelian randomization approach, we assessed differences in genotypically-estimated relative LTL in two independent glioma case-control datasets from the UCSF Adult Glioma Study (652 patients and 3735 controls) and The Cancer Genome Atlas (478 non-overlapping patients and 2559 controls). LTL estimates were based on a weighted linear combination of subject genotype at eight SNPs, previously associated with LTL in the ENGAGE Consortium Telomere Project. Mean estimated LTL was 31bp (5.7%) longer in glioma patients than controls in discovery analyses (P = 7.82 × 10-8) and 27bp (5.0%) longer in glioma patients than controls in replication analyses (1.48 × 10-3). Glioma risk increased monotonically with each increasing septile of LTL (O.R.=1.12; P = 3.83 × 10-12). Four LTL-associated SNPs were significantly associated with glioma risk in pooled analyses, including those in the telomerase component genes TERC (O.R.=1.14; 95% C.I.=1.03-1.28) and TERT (O.R.=1.39; 95% C.I.=1.27-1.52), and those in the CST complex genes OBFC1 (O.R.=1.18; 95% C.I.=1.05-1.33) and CTC1 (O.R.=1.14; 95% C.I.=1.02-1.28). Future work is needed to characterize the role of the CST complex in gliomagenesis and further elucidate the complex balance between ageing, telomere length, and molecular carcinogenesis.

KW - CST complex

KW - Glioma

KW - Single nucleotide polymorphism

KW - Telomerase

KW - Telomere

UR - http://www.scopus.com/inward/record.url?scp=84952332384&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84952332384&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.6468

DO - 10.18632/oncotarget.6468

M3 - Article

C2 - 26646793

AN - SCOPUS:84952332384

VL - 6

SP - 42468

EP - 42477

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 40

ER -