PO.CL01.07 · 临床研究
表征肝细胞癌患者的cfDNA片段组
Characterizing the cfDNA fragmentome in patients with hepatocellular carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肝细胞癌（HCC）是全球癌症死亡的第三大原因，并且由于代谢性和新兴危险因素，是北美和欧洲增长最快的癌症死亡原因之一。在此，我们展示了循环游离DNA（cfDNA）片段化图谱反映潜在的疾病生物学特征，并且一个机器学习分类器可在不同人群中检测HCC，通过纳入患者临床风险和蛋白浓度而得到增强。cfDNA片段组的特征，包括全基因组染色质、重复元件、甲基化组和突变图谱，在HCC患者中发生改变，包括具有代谢危险因素和黄曲霉毒素暴露的患者。新颖的全基因组组织起源解卷积分析发现，癌症患者中源自肝细胞（p=2.4x10^-10）和CD8+ T细胞（p=5.8x10^-7）的cfDNA代表性增加，而NK细胞的贡献减少（p=3.0x10^-6）。使用先前锁定的肝癌检测片段组分类器，我们分析了来自两个不同地理队列的377名有和无HCC的个体。我们发现cfDNA片段组分类器可在所有分期和多种病因中检测HCC，灵敏度为70%（95% CI=65%-75%），特异性为94%（95% CI=90%-97%），优于常用的甲胎蛋白（AFP）生物标志物（灵敏度62%，95% CI=57%-67%；特异性93%，95% CI=88%-96%）。在两个队列中，结合cfDNA片段组、AFP和临床风险的组合方法在可移植治愈疾病（米兰标准）中实现了74%的灵敏度（95% CI=66%-80%）和85%的特异性（95% CI=78%-89%），并且在早期疾病中比标准治疗的AFP和超声表现更灵敏（报告为84%特异性下63%灵敏度）。本研究为肝癌高风险人群中cfDNA和循环蛋白改变的起源提供了见解，并支持使用全基因组片段组方法进行HCC的非侵入性检测。
查看英文原文 English abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally and is one of the most rapidly increasing causes of cancer mortality in North America and Europe due to metabolic and emerging risk factors. Here, we show that cell-free DNA (cfDNA) fragmentation profiles reflected underlying disease biology and that a machine learning classifier detected HCC across diverse populations and was enhanced by incorporating patient clinical risk and protein concentrations. Characteristics of the cfDNA fragmentome, including genome-wide chromatin, repeat elements, methylome, and mutational profiles, were altered in patients with HCC, including those with metabolic risk factors and aflatoxin exposure. Novel whole-genome tissue-of-origin deconvolution analyses identified increased representation of cfDNA originating from hepatocytes (p=2.4x10 -10 ) and CD8+ T cells (p=5.8x10 -7 ) and decreased contribution of NK cells (p=3.0x10 -6 ) in patients with cancer. Using a previously locked fragmentome classifier for liver cancer detection, we analyzed 377 individuals with and without HCC from two distinct geographic cohorts. We found that the cfDNA fragmentome classifier detected HCC across all stages and diverse etiologies with a sensitivity of 70% (95% CI=65%-75%) and specificity of 94% (95% CI=90%-97%), outperforming the commonly used alpha-fetoprotein (AFP) biomarker which had a sensitivity of 62% (95% CI=57%-67%) and specificity of 93% (95% CI=88%-96%). A combined approach using cfDNA fragmentomes, AFP, and clinical risk achieved a sensitivity of 74% (95% CI=66%-80%) at a specificity of 85% (95% CI=78%-89%) in transplant curable disease (Milan criteria) in both cohorts and was more sensitive than standard-of-care AFP and ultrasound performance for early-stage disease (reported 63% sensitivity at 84% specificity). This study provides insights into the origins of altered cfDNA and circulating proteins for populations at risk of liver cancer and supports the use of a genome-wide fragmentome approach for non-invasive detection of HCC.
利益披露 Disclosure
H. Orjuela, None..
C. Norton, None..
S. Koul, None.
D. C. Bruhm,
Delfi Diagnostics Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics.
A. V. Annapragada,
Delfi Diagnostics Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics..
S. Short, None..
K. Boyapati, None..
A. Bartolomucci, None.
V. Adleff,
Delfi Diagnostics Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics. Founder of Delfi Diagnostics and consultant for this organization..
N. A. Vulpescu, None..
K. Lebarbenchon, None.
J. Carey,
Delfi Diagnostics Stock.
C. Portwood, None..
A. Sorop, None..
R. Iacob, None..
S. Iacob, None..
L. Gheorghe, None..
S. Dima, None..
K. A. McGlynn, None..
M. Ramirez-Zea, None.
J. Phallen,
Delfi Diagnostics Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics. Founder of Delfi Diagnostics.
R. B. Scharpf,
Delfi Diagnostics Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics. Founder of Delfi Diagnostics and consultant for this organization.
J. Groopman, None.
V. E. Velculescu,
Delfi Diagnostics g., Board of Directors, non-salaried role), Stock, Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also an inventor on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics. Founder of Delfi Diagnostics.
Personal Genome Diagnostics (PGDx) Other, Divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022.
LabCorp Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to LabCorp.
Qiagen Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to Qiagen.
Sysmex Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to Sysmex.
Agios Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to Agios.
Genzyme Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to Genzyme.
Esoterix Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to Esoterix.
Ventana Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to Ventana.
ManaT Bio Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cancer genomic and cell-free DNA analyses that have been licensed to ManaT Bio.
Viron Therapeutics Other, Advisor.
Epitope Other, Advisor.
Z. Foda,
Delfi Diagnostics Patent, Other, Inventor on patent applications submitted by Johns Hopkins University related to cell-free DNA analyses. Also on patent applications submitted by Johns Hopkins University related to cfDNA and cancer detection that have been licensed to Delfi Diagnostics.