PO.BCS01.13 · 生物信息与计算
组织和血浆游离DNA中端粒长度的泛癌图谱
A pan-cancer atlas of telomere length in tissues and plasma cell-free DNA
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
由于复制不完全和端粒酶活性有限，端粒随年龄缩短，其功能障碍促进癌症中的基因组不稳定性。现有的估计方法依赖严格的重复序列计数，常常遗漏受错误影响或生物学上缩短的片段。这在血浆cfDNA中尤为棘手，因为大多数片段约为170 bp，而ctDNA甚至更短（Cristiano等，2019；Chabon等，2020）。基于纳米孔的检测提供了精确测量（Sanchez等，2024；Karimian等，2024），但准确、容错的短读长方法仍未得到满足。
方法：
我们开发了VERACITY，一种机器学习方法，通过对端粒重复模式和测序错误谱建模，从短读长WGS估计端粒长度（TL）。VERACITY还计算端粒模糊指数（TAI），以量化端粒维持的异质性。我们将VERACITY应用于27种癌症类型的10,363个TCGA WGS样本（4,847个肿瘤；5,089个匹配正常组织；年龄14-85岁）、3个经系统降采样的深度（约200×）cfDNA基因组，以及来自DELFI队列的462个低覆盖（2-3×）cfDNA基因组（233例癌症；229例健康；年龄14-86岁），生成了组织和血浆中端粒生物学的图谱。
结果：
降采样显示可靠的TL估计可降至约2.5×覆盖度，支持低覆盖cfDNA应用。组织和cfDNA的趋势高度一致。在各类癌症中，肿瘤及其匹配正常组织的TL均随年龄下降，而肿瘤显示出更为陡峭的侵蚀（组织肿瘤：beta_age = -62.5*，beta_age² = 0.5* 对比 正常：-10.8，0.02；cfDNA癌症：-13 对比 健康：0 bp）。男性肿瘤显示出比女性肿瘤更大的丢失（TCGA：-90.0*，0.66*；cfDNA：-99.1*，0.8）（女性肿瘤 TCGA：-15.5，0.16；cfDNA：-0.9，-0.1）。
年龄相关的轨迹差异很大：GBM、TGCT和STAD显示出陡峭的非线性下降，而CESC、KICH和LGG显示出极小或正的斜率，与调整后的TL残差一致。尽管胃组织显示出最弱的TL-年龄相关性（Demanelis等，2020），胃癌在组织（beta_age = -135.2 bp）和cfDNA（-63.5 bp）中均表现出最强的下降之一，且Gini和ATR值属最低之列。若干癌症，包括PRAD和TGCT，显示出升高的TAI，提示存在多样或不稳定的维持策略。
结论：
VERACITY为从标准和低覆盖测序中估计TL提供了准确且可扩展的框架，实现了迄今为止最全面的跨癌症组织与血浆端粒动态图谱。分析揭示了加速的、按性别分层的、癌症类型特异性的端粒侵蚀，显著的肿瘤间异质性，以及不同的维持机制。cfDNA TL模式与组织衍生趋势高度吻合，凸显了端粒指标作为端粒功能障碍、肿瘤生物学及治疗相关端粒状态的微创生物标志物的潜力。
查看英文原文 English 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: beta_age = -62.5*, beta_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 (beta_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.
利益披露 Disclosure
J. Shi, None..
L. Espinoza, None.