PO.CL01.07 · 临床研究

Characterizing the cfDNA fragmentome in patients with hepatocellular carcinoma

编号 1125 展板 6 时间 4/19 02:00–05:00 区域 Section 44 主讲 Hope Orjuela, BA

分会场 Liquid Biopsies: Circulating Nucleic Acids 1

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作者与单位

Hope Orjuela¹, Carter Norton¹, Shashikant Koul¹, Daniel C. Bruhm¹, Akshaya V. Annapragada¹, Sarah Short¹, Keerti Boyapati¹, Adrianna Bartolomucci¹, Vilmos Adleff¹, Nicholas A. Vulpescu¹, Kauí Lebarbenchon¹, Jacob Carey², Carter Portwood², Andrei Sorop³, Razvan Iacob³, Speranta Iacob³, Liana Gheorghe³, Simoni Dima³, Katherine A. McGlynn⁴, Manuel Ramirez-Zea⁵, Jillian Phallen¹, Robert B. Scharpf¹, John Groopman¹, Victor E. Velculescu¹, Zachariah Foda¹

¹The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD,²DELFI Diagnostics, Baltimore, MD,³Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania,⁴Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD,⁵Research Center for the Prevention of Chronic Diseases, Institute of Nutrition of Central American and Panama (INCAP), Guatemala City, Guatemala

摘要 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.

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