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.

Genome-Wide Association Studies in Glioma

“…The risk allele of rs11598018 ( C ) is associated with increased leukocyte telomere length thereby supporting a relationship between genotype and biology (78–80). Variation at 10q24.33 is additionally associated with risk of melanoma (81), basal cell carcinoma (82), thyroid cancer (83), and renal cell carcinoma (84).…”

Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia

“…The effect size used for weighting was expressed as the number of additional base-pairs of telomere length associated with each allele, adjusted for age and sex, as calculated and previously reported by the ENGAGE Consortium Telomere Group (12, 17). The number of base-pairs was used because the model can be interpreted as the relative difference in estimated LTL across individuals.…”

“…Additionally, while the effect of individual alleles in telomere-maintenance genes may be small, the combined effect of numerous such polymorphisms could potentially be quite large and could help identify the “missing heritability” of cancer(16). This Mendelian randomization approach for examining the relationship between telomere length and cancer risk has been previously applied to glioma, melanoma and lung adenocarcinoma, but not to hematologic malignancies (17–19). …”

Understanding TERT Promoter Mutations: A Common Path to Immortality

“…The cancers found to be telomerase negative use an alternative mechanism of telomere lengthening termed ALT(21–23). Furthermore, germline variation in genes involved in telomere regulation such as RTEL1, POT1, TERC, TERT, and genes of the CST complex underlies increased risk of glioma (24–27), melanoma(28), and cancers of the lung(29,30), bladder(28), and pancreas(31). …”