Abstract 6892: A pan-cancer atlas of telomere length in tissues and plasma cell-free DNA.

Abstract Background: Telomeres shorten with age because of incomplete replication and limited telomerase activity, and their dysfunction promotes genomic instability in cancer. Existing estimators rely on strict repeat counts and often miss error-affected or biologically shortened fragments. This is problematic in plasma cfDNA where most fragments are ∼170 bp and ctDNA is even shorter (Cristiano et al., 2019; Chabon et al., 2020). Nanopore-based assays provide precise measurement (Sanchez et al., 2024; Karimian et al., 2024), but an accurate, error-tolerant short-read approach remains unmet. Methods: We developed VERACITY, a machine-learning method that estimates telomere length (TL) from short-read WGS by modeling telomeric-repeat patterns and sequencing-error profiles. VERACITY also computes a Telomere Ambiguity Index (TAI) that quantifies heterogeneity in telomere maintenance. We applied VERACITY to 10,363 TCGA WGS samples (4,847 tumors; 5,089 matched normals; ages 14-85) across 27 cancer types, 3 deep (∼200×) cfDNA genomes with systematic down-sampling, and 462 low-pass (2-3×) cfDNA genomes from the DELFI cohort (233 cancers; 229 healthy; ages 14-86), generating an atlas of telomere biology in tissues and plasma. Results: Down-sampling showed reliable TL estimation down to ∼2.5× coverage, supporting low-pass cfDNA application. Tissue and cfDNA trends were highly concordant. Across cancers, TL declined with age in tumors and matched normals, with tumors showing far steeper erosion (tissue tumor: β_age = -62.5*, β_age2 = 0.5* vs. normal: -10.8, 0.02; cfDNA cancer: -13 vs. healthy: 0 bp). Male tumors showed greater loss (TCGA: -90.0*, 0.66*; cfDNA: -99.1*, 0.8) than female tumors (TCGA: -15.5, 0.16; cfDNA: -0.9, -0.1). Age-associated trajectories varied widely: GBM, TGCT, and STAD showed steep nonlinear declines, whereas CESC, KICH, and LGG showed minimal or positive slopes, consistent with adjusted TL residuals. Although stomach tissues show the weakest TL-age correlation (Demanelis et al., 2020), gastric cancers exhibited one of the strongest declines in both tissue (β_age = -135.2 bp) and cfDNA (-63.5 bp) and among the lowest Gini and ATR values. Several cancers, including PRAD and TGCT, displayed elevated TAI, suggesting diverse or unstable maintenance strategies. Conclusions: VERACITY provides an accurate and scalable framework for TL estimation from standard and low-pass sequencing, enabling the most comprehensive atlas to date of telomere dynamics across cancers in tissues and plasma. The analysis reveals accelerated, sex-stratified, and cancer-type-specific telomere erosion, substantial inter-tumor heterogeneity, and distinct maintenance mechanisms. cfDNA TL patterns closely mirror tissue-derived trends and highlight the potential of telomere metrics as minimally invasive biomarkers of telomere dysfunction, tumor biology, and treatment-relevant telomere states. Citation Format: Junming Shi, Leslie Espinoza, Mengran Zhang, Mohammad Shahrokh Esfahani, . A pan-cancer atlas of telomere length in tissues and plasma cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6892.