Defining cancer risk germline variants in shelterin complex genes - a genome-first analysis

Background : The shelterin complex (encoded by ACD, POT1, TERF1, TERF2, TERF2IP, andTINF2) is essential for telomere maintenance and chromosome stability. Pathogenic or likelypathogenic (P/LP) germline variants in some shelterin genes cause telomere biology disorders aswell as cancer predisposition with long telomeres. To date, studies have focused on clinicallyascertained families. Genome-first approaches identify individuals with rare P/LP variants frompopulation-scale sequencing databases linked to electronic health records, enabling better estimates of variant prevalence and cancer risk. Methods : We assessed rare (minor allele frequency<1%) P/LP germline variants in ACD,TERF1, TERF2, TERF2IP, and TINF2. Exome and phenotype data were analyzed from UKBiobank (UKB) (N=469,578) and Geisinger DiscovEHR cohort (N=216,361). Variants wereclassified using AutoGVP and literature review. Cancer prevalence and risk in carriers versusnoncarriers were evaluated using logistic regression models, respectively, adjusted for year ofbirth, sex, smoking status, alcohol intake, body mass index, and genetically determined ancestry. Results : We identified 1,200 individuals (784 in UKB and 416 in Geisinger) with P/LP germlinevariants in shelterin complex genes. The prevalence of shelterin variants ranged from 1:1,886 to1:39,132 in UKB and 1:1,157 to 1:24,040 in Geisinger, ACD and TINF2 had the highestestimates and TERF2 the lowest. In ACD, a variant previously associated with cancer(c.488A>G, p.Asn163Ser) accounted for 49.3% of all ACD carriers. In UKB, TINF2 carriers hadsignificantly increased risk for melanoma (OR 5.33 (1.93-14.70); p=0.015), endocrine cancers(OR 25.30 (9.16-69.87); p<0.001), and mesothelioma (OR 18.38 (2.47-137.02); p=0.036) anddemonstrated overall earlier ages at cancer onset than noncarriers (p=0.0036). In Geisinger,TINF2 was associated with increased risk of cancers of soft tissue including heart (OR 6.76 (1.65-27.60); p=0.01), liver/ bile duct (OR 3.28 (1.03-10.50); p=0.05), and brain/nervous system(OR 5.19 (1.89-14.20); p<0.001). In Geisinger, ACD carriers with c.488A>G had an increasedrisk of eye and orbit cancers (OR 15.27 (2.10-111.00); p=0.007), although there was only onecarrier. The number of cancer events among individuals with TERF1, TERF2, and TERF2IPvariants was insufficient for statistical analyses. Conclusion : In Geisinger, prevalence of rare P/LP shelterin gene variants was generally higherthan in UKB, reflecting the clinically enriched nature of that cohort. TINF2 had variants with thestrongest cancer associations. Longitudinal studies of younger cohorts are warranted to refineprevalence estimates and cancer risk associated with shelterin complex genes.