Predicted leukocyte telomere length and risk of germ cell tumours

Abstract

Background: Genetically predicted leukocyte telomere length (LTL) has been evaluated in several studies of childhood and adult cancer. We test whether genetically predicted longer LTL is associated with germ cell tumours (GCT) in children and adults.

Methods: Paediatric GCT samples were obtained from a Children's Oncology Group study and state biobank programs in California and Michigan (N = 1413 cases, 1220 biological parents and 1022 unrelated controls). Replication analysis included 396 adult testicular GCTs (TGCT) and 1589 matched controls from the UK Biobank. Mendelian randomisation was used to look at the association between genetically predicted LTL and GCTs and TERT variants were evaluated within GCT subgroups.

Results: We identified significant associations between TERT variants reported in previous adult TGCT GWAS in paediatric GCT: TERT/rs2736100-C (OR = 0.82; P = 0.0003), TERT/rs2853677-G (OR = 0.80; P = 0.001), and TERT/rs7705526-A (OR = 0.81; P = 0.003). We also extended these findings to females and tumours outside the testes. In contrast, we did not observe strong evidence for an association between genetically predicted LTL by other variants and GCT risk in children or adults.

Conclusion: While TERT is a known susceptibility locus for GCT, our results suggest that LTL predicted by other variants is not strongly associated with risk in either children or adults.

Fig. 1. Association between individual single nucleotide polymorphisms (SNPs) that genetically predict leukocyte telomere length (LTL) and paediatric germ cell tumour (GCT) risk: results from the Mendelian Randomization (MR) analysis.

a, b Presents results using SNPs from the Codd et al. [27] genetic instrument excluding TERT and c, d presents results using SNPs from the Li et al. [32] genetic instrument excluding TERT. Forest plots (left) show the effect estimate per variant using MR Wald Ratio single SNP test, and overall MR estimates using MR Egger, weighted median, and inverse-variance-weighted (IVW) estimators (N = 1413). Odds ratio is for every 1 kb increase in LTL. Scatter plots (right) show the per-allele association with paediatric GCT risk (outcome) plotted against the per‐allele association with kb of LTL (exposure). The vertical and horizontal grey lines represent the standard error for each SNP. The slope of the scatter plot is overlaid with the Mendelian randomisation IVW estimate (solid black line), the MR Egger estimate (dotted black line) and the weighted median estimate (dashed black line) of the effect of LTL on GCT risk.

Fig. 2. Sub-group specific association between genetically predicted leukocyte telomere length (LTL) and paediatric germ cell tumour (GCT) risk: results from the Mendelian Randomization (MR) analysis.

a Presents results using single nucleotide polymorphisms (SNPs) from the Codd et al. [27] genetic instrument excluding TERT and b presents results using SNPs from Li et al. [32] genetic instrument excluding TERT. Forest plots (left) show the effect estimate per subgroup from the meta-analysis, and overall MR estimates using MR Egger, weighted median, and inverse-variance-weighted (IVW) estimators (N = 1413). Odds ratio is for every 1 kb increase in LTL. Footnote: Sample size indicated in parenthesis (n = #) represents the total number of cases which includes those in the complete trios and in the case–control analyses. Subgroup analysis included trios, Hispanic and White case–control only samples to get stable estimates. African American and Asian case–control samples were not included in subgroup analyses (only overall analyses) due to the small sample size.

Fig. 3. Association between individual single nucleotide polymorphisms (SNPs) that genetically predict leukocyte telomere length (LTL) and UKB testicular germ cell tumour (TGCT) risk: results from the Mendelian Randomization analysis.

a, b Presents results using SNPs from the Codd et al. [27] genetic instrument excluding TERT and c, d presents results using SNPs from the Li et al. [32] genetic instrument excluding TERT. Forest plots (left) show the effect estimate per variant using MR Wald Ratio single SNP test, and overall MR estimates using MR Egger, weighted median, and inverse-variance-weighted (IVW) estimators (N = 396). Odds ratio is for every 1 kb increase in LTL. Scatter plots (right) show the per-allele association with paediatric GCT risk (outcome) plotted against the per‐allele association with kb of LTL (exposure). The vertical and horizontal grey lines represent the standard error for each SNP. The slope of the scatter plot is overlaid with the Mendelian randomisation IVW estimate (solid black line), the MR Egger estimate (dotted black line) and the weighted median estimate (dashed black line) of the effect of LTL on GCT risk.

Fig. 4. Meta-analysis results for subgroup-specific associations between TERT single nucelotide polymorphisms (SNPs) and germ cell tumor (GCT) risk.

Odds ratios (OR and 95% CI) are presented as the risk allele associated with longer telomere length. a TERT SNP from Codd et al. 2013 and b, c TERT SNPs from Li et al. 2020. Footnote: Sample size indicated in parenthesis (n = #) represents the total number of cases which includes those in the complete trios and in the case–control analyses. Subgroup analysis included trios, Hispanic and White case–control only samples to get stable estimates. African American and Asian case–control samples were not included in subgroup analyses (only overall analyses) due to the small sample size.