Abstract 874: Predicted leukocyte telomere length and risk of germ cell tumors
Authors: Cigan Shannon S. , Kelley Ava C. , Meredith John J. , Langer Erica K. , Hooten Anthony J. , Lane John A. , Cole Benjamin R. , Pankratz Nathan , Poynter Jenny 
Published: July 2021

Abstract
Genetically predicted leukocyte telomere length (LTL) has been evaluated in a number of studies of childhood and adult cancer, with evidence that longer predicted LTL is associated with increased cancer risk. We use Mendelian Randomization (MR) to test whether genetically predicted LTL is associated with germ cell tumors (GCT) in pediatric, adolescent, and adult cases using six SNPs that are validated predictors of LTL. A seventh SNP in the validated genetic predictor of LTL, rs2736100, a variant on TERT, is associated with adult testicular GCT (TGCT); therefore, in our overall analysis, we removed this SNP to avoid violating MR assumptions.
Pediatric GCT samples were obtained from a Children's Oncology Group study and state biobank programs in Michigan and California. Genotyping array data were generated using the Illumina HumanCoreExome Beadchip. For each SNP, we estimated main effects for pediatric GCT within 610 complete case-parent trios using the transmission disequilibrium test. We did the same in an independent case-control dataset of 803 pediatric cases and 1,022 controls stratified by ancestry using multivariable logistic regression adjusted for sex, ancestry-specific principal components (PCs), and study site. Effect estimates were meta-analyzed and used to perform the MR analyses. In a separate sample of 396 cases and 1,589 matched controls from the UK Biobank, genotyping array data was used to evaluate the association between a polygenic risk score capturing genetically predicted LTL and TGCT in men &lt;50 years old using multivariable logistic regression adjusted for global ancestry PCs (PC1-10). We observed a positive association between LTL and overall risk of GCT in both the pediatric cases (OR [95% CI] = 2.52 [1.19, 5.34] per kb of LTL; p=0.016) and the adult TGCT cases (OR [95% CI] = 1.94 [0.60, 6.28] per kb of LTL; p=0.266). Subgroup analyses in our pediatric GCT cases show consistent findings of longer LTL and risk across subgroups, with the exception of teratomas. Additionally, we evaluated the individual SNP effect of TERT/rs2736100-A and observed a significant association in pediatric GCT (OR [95% CI] = 1.21 [1.09, 1.35]; p =0.0003) which is driven by male cases diagnosed in adolescence (age at dx 11-19 years). A significant association was also observed between TERT/rs2736100-A and adult TGCT (OR [95% CI] = 1.25 [1.07, 1.46]; p=0.005). Similar to analyses of other childhood and adult cancers, our results indicate that longer telomere length is associated with an increased risk of GCT in pediatric, adolescent, and adult GCT. We also observed a strong association between pediatric GCT and TERT and confirmed previous findings with adult TGCT. These results indicate further analyses of variants in genes relevant for telomere function and maintenance are warranted.
Citation Format: Shannon S. Cigan, Ava C. Kelley, John J. Meredith, Erica K. Langer, Anthony J. Hooten, John A. Lane, Benjamin R. Cole, Nathan Pankratz, Jenny Poynter. Predicted leukocyte telomere length and risk of germ cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 874.