Abstract 4891: Genome-first approach identifies shelterin complex gene variants and associated cancers

Abstract Telomeres, nucleotide repeats and a six-protein complex called shelterin at chromosome ends, are critical for genomic integrity. Rare heterozygous pathogenic or likely pathogenic (P/LP) germline variants in shelterin complex genes have been associated with long telomeres and risk of certain cancers, including melanoma, lymphoproliferative diseases, glioma, papillary thyroid cancer, and sarcoma. Traditional phenotype-first studies of P/LP germline variants and disease are often limited by ascertainment of the most severely affected individuals. Genome-first approaches can reduce this bias by first assessing germline variants and then evaluating the associated diseases. Since most studies, to date, have focused on variants in POT1 and cancer, we sought to estimate associations between cancer and rare P/LP variants in the five less well studied shelterin genes (ACD, TERF1, TERF2, TERF2IP, and TINF2) in the UK Biobank (UKB) to understand their role in cancer etiology at the population level. Exome sequencing data on 469, 578 participants were retrieved from the UKB DNA Nexus platform. Variants with minor allele frequency <1%, exonic or splice site, genotype quality >30, depth >20, and allele fraction >0.3 were retained. Variant classification used Automated Germline Variant Pathogenicity (PMID: 38426335). Logistic regression analyses adjusted for age, sex, alcohol use, smoking, and BMI were used to calculate odds ratios (OR) and 95% confidence intervals (CI). There were 177 participants (97 female, 80 male, median age = 57.0 years, range = 40.0 - 69.0) with 59 unique P/LP germline variants (30 ACD, 9 TERF2, and 20 TINF2). Strikingly, there were no rare variants in TERF1 or TERF2IP. The population prevalence of individuals with P/LP germline variants in these five shelterin genes is estimated at 1:2, 514 (174/437, 486 unrelated individuals, 95% CI 2, 189-2, 953). Forty-eight individuals with P/LP germline variants were diagnosed with at least one cancer with a median age at first cancer of 59.3 years (range 19.4 - 80.6). Overall, P/LP variants were significantly associated with melanoma (OR 2.93, 95% CI 1.20-7.15, p = 0.018) and cancers of the urinary system (OR 2.78, 1.02-7.57, p = 0.045). By gene, P/LP variants were associated with cancers of the oral cavity/pharynx (ACD, OR 4.78, 95% CI 1.18-19.4, p = 0.030), soft tissue including heart (ACD, OR 8.90, 95% CI 1.24-63.9, p = 0.030), colon excluding the rectum (TERF2, OR 8.44 , 95%CI 1.05-68.0, p= 0.045), female genital system (TERF2, OR 12.98, 95% CI 1.43-117.8, p = 0.023), and melanoma (TINF2, OR 7.63, 2.35-24.75, p = 0.001).Rare P/LP germline variants in ACD, TERF2, and TINF2 may be associated with increased risk of certain cancers in the UKB. Analyses applying the genome-first approach other population-based cohorts and assessment of telomere length are underway to better understand the extent to which variation in shelterin genes contributes to cancer etiology. Citation Format: Akanksha Nagarkar, Hasset Nurelegne, Jung Kim, Kelvin C. de Andrade, Sharon A. Savage. Genome-first approach identifies shelterin complex gene variants and associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4891.