PO.CL01.07 · 临床研究

来自血液和唾液的全基因组无细胞DNA片段组学实现头颈癌的早期检测

Genome-wide cell-free DNA fragmentomes from blood and saliva enable early detection of head and neck cancers

编号 1145 展板 26 时间 4/19 02:00–05:00 区域 Section 44 主讲 Akshaya Annapragada, BA;MS

分会场 Liquid Biopsies: Circulating Nucleic Acids 1

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作者与单位 Authors & Affiliations

Akshaya Vijaya Annapragada¹, Shanaya Patel², Sarah Short¹, Keerti Boyapati¹, Shashi Koul¹, Hope Orjuela¹, Alice Eastman¹, Aditi Patel², Shreya Lotia², Vaishnavi Patel², Jason Zavras¹, Adrianna Bartolomucci¹, Dushyant Mandlik³, Kaustubh Patel³, Vivek Tanavde², David Sidransky¹, Mariana Brait¹, Rob Scharpf¹, Victor Velculescu¹, Jillian Phallen¹

¹Johns Hopkins University School of Medicine, Baltimore, MD,²Ahmedabad University, Ahmedabad, India,³HCG Cancer Centre, Ahmedabad, India

摘要 Abstract

中文摘要

引言：全球超过十亿人受到头颈部鳞状细胞癌（HNSCC）风险因素的影响——主要为吸烟和无烟烟草、酒精及人乳头瘤病毒（HPV）——若有筛查项目，这些人群可能从中获益（在各肿瘤部位，早期相较转移性疾病的五年生存率翻倍以上，但目前仅30%的癌症在早期被诊断）。我们此前基于无细胞DNA（cfDNA）片段化特征（DELFI）和重复序列图谱（ARTEMIS）开发了针对多种癌症类型的非侵入性血液检测。这些检测使用经济高效的低覆盖度全基因组测序（WGS）来分析数百万条cfDNA片段，其长度、组成及全基因组分布反映了癌症相关的遗传和表观遗传改变。在此，我们将这些分析扩展到另一种非侵入性采样的体液——唾液，并展示其在HNSCC检测中的应用。方法：我们建立了一个前瞻性单中心采集队列，收集患有和未患HNSCC个体的血液和唾液样本（n=329）。其中包括68例无高危暴露的健康个体、62例使用咀嚼烟草的健康个体、17例高危白斑个体，以及182例癌症个体，包括分别处于HNSCC I-IV期的39例、37例、27例和79例。我们从血液（全部，n=329）和唾液（子集，n=96）中提取cfDNA，进行低覆盖度WGS，并将个体分为发现队列（n=244）和验证队列（n=85）。我们评估了血液和唾液中的全基因组片段化特征（DELFI）和重复序列图谱（ARTEMIS）。我们在发现队列中，使用血液、唾液或（当两种体液均可用时）来自两种体液的特征，对三个ARTEMIS-DELFI分类器进行交叉验证，并在留出的验证队列中评估锁定的模型。结果：来自同一患者的血液和唾液样本的全基因组片段组具有一致性（中位相关系数r=0.76，IQR 0.64 - 0.87），并反映了癌症相关改变，包括8q获得以及3p和9p缺失等染色体改变。在发现队列中，HNSCC个体被高性能地检出（血浆和唾液的AUC分别为0.87，95% CI=0.83-0.91，以及AUC=0.85，95% CI=0.76-0.94），而使用两种体液特征的组合模型达到0.89的AUC（95% CI 0.82-0.97）。在验证队列中，在对应90%特异性的锁定阈值下，血液、唾液和组合模型分别检出65%、71%和71%的癌症。在各队列中，所有模型对I期肿瘤的敏感性均≥50%。结论：我们证明了cfDNA片段化特征和重复序列图谱可从血液和唾液中获取。这些方法可能为全球高危人群实现可及、高性能的HNSCC筛查。

查看英文原文 English abstract

INTRODUCTION: Over a billion people globally are impacted by risk factors for head and neck squamous cell carcinoma (HNSCC) - primarily smoking and smokeless tobacco, alcohol and human papillomavirus (HPV) - and may benefit from screening programs if they were available (five-year survival more than doubles for early-stage compared to metastatic disease across tumor sites but currently only 30% of cancers are diagnosed in early stages). We previously developed non-invasive blood tests for multiple cancer types using cell-free DNA (cfDNA) fragmentation profiles (DELFI) and repeat landscapes (ARTEMIS). These tests use cost-effective low-coverage whole-genome sequencing (WGS) to analyze millions of cfDNA fragments whose length, composition, and genome-wide distribution reflect cancer-related genetic and epigenetic changes. Here, we expand these analyses to another non-invasively sampled biofluid, saliva, and demonstrate their use for HNSCC detection. METHODS: We established a prospective single-center collection of blood and saliva samples from individuals with and without HNSCC (n=329). These include 68 healthy individuals without high-risk exposures, 62 healthy individuals who use chewing tobacco, 17 individuals with high-risk leukoplakia, and 182 individuals with cancer, including 39, 37, 27, and 79 with stages I-IV of HNSCC respectively. We extracted cfDNA from blood (all, n=329) and saliva (subset, n=96), performed low-coverage WGS, and split individuals into Discovery (n=244) and Validation (n=85) cohorts. We evaluated genome-wide fragmentation profiles (DELFI) and repeat landscapes (ARTEMIS) in blood and saliva. We cross-validated three ARTEMIS-DELFI classifiers using blood, saliva, or features from both biofluids when available in the Discovery Cohort, and evaluated the locked models in the held-out Validation Cohort. RESULTS: Genome-wide fragmentomes were concordant between blood and saliva samples from the same patients (median correlation coefficient r=0.76, IQR 0.64 - 0.87), and reflected cancer-related alterations including chromosomal changes such as 8q gain and 3p and 9p loss. In the Discovery Cohort, individuals with HNSCC were detected with high performance (AUC=0.87, 95% CI=0.83-0.91 and AUC=0.85, 95% CI=0.76-0.94 for plasma and saliva, respectively), and a combined model using features from both biofluids achieved an AUC of 0.89 (95% CI 0.82-0.97). In the Validation Cohort, at locked thresholds corresponding to 90% specificity, 65%, 71%, and 71% of cancers were detected by the blood, saliva and combined models, respectively. Across cohorts, sensitivity for Stage I tumors was >= 50% for all models. CONCLUSIONS: We demonstrated that cfDNA fragmentation profiles and repeat landscapes can be obtained from both blood and saliva. These approaches may enable accessible, high-performance screening for HNSCC in global high-risk populations.

利益披露 Disclosure

A. V. Annapragada, DELFI Diagnostics, Artemyx Stock, Patent, A.V.A. is a co-founder of Artemyx. A.V.A. is an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and disease detection that have been licensed to Delfi Diagnostics and Artemyx.. S. Patel, None.. S. Short, None.. K. Boyapati, None.. S. Koul, None.. H. Orjuela, None.. A. Eastman, None.. A. Patel, None.. S. Lotia, None.. V. Patel, None.. J. Zavras, None.. A. Bartolomucci, None.. D. Mandlik, None.. K. Patel, None.. V. Tanavde, None.. D. Sidransky, None.. M. Brait, None. R. Scharpf, DELFI Diagnostics, Artemyx Employment, g., Board of Directors, non-salaried role), Stock, ), Patent, R.B.S. is a co-founder of Artemyx. R.B.S. is an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and disease detection that have been licensed to Delfi Diagnostics and Artemyx. R.B.S. is a founder of DELFI Diagnostics and consultant for this organization. V. Velculescu, DELFI Diagnostics, Artemyx, PGDx Employment, g., Board of Directors, non-salaried role), Stock, Stock Option, Other Business Ownership, ), Patent, V.E.V. is a founder of Delfi Diagnostics and Artemyx, serves on the Board of Directors for both organizations, as an officer for Artemyx, and owns Delfi Diagnostics and Artemyx stock. V.E.V. divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022.. Consulting/Advisory Employment, ), Patent, Other, V.E.V. is an inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to one or more entities, including Delfi Diagnostics, Artemyx, LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana and ManaT Bio. V.E.V. is an advisor to Viron Therapeutics and Epitope. J. Phallen, DELFI Diagnostics, Artemyx g., Board of Directors, non-salaried role), Stock, Patent, J.P. is a co-founder of Artemyx. J.P.. is an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and disease detection that have been licensed to Delfi Diagnostics and Artemyx. J.P.. is a founder of DELFI Diagnostics. .

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