Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases
Abstract
Multiple case-controlled studies have shown that analyzing fragmentation patterns in plasma cell-free DNA (cfDNA) can distinguish individuals with cancer from healthy controls. However, there have been few studies that investigate various types of cfDNA fragmentomics patterns in individuals with other diseases. We therefore developed a comprehensive statistic, called fragmentation signatures, that integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA. We found that individuals with venous thromboembolism, systemic lupus erythematosus, dermatomyositis, or scleroderma have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers. Furthermore, these signatures were highly correlated with increases in inflammatory markers in the blood. We demonstrate that these similarities in fragmentation signatures lead to high rates of false positives in individuals with autoimmune or vascular disease when evaluated using conventional binary classification approaches for multicancer earlier detection (MCED). To address this issue, we introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers and achieves improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity. Though these data put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, they also offer ways to improve the interpretability of such tests. Moreover, we expect these results will lead to a better understanding of the process—most likely inflammatory—from which abnormal fragmentation signatures are derived.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (41)
Samuel D. Curtis
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine
Tingshan Liu
Department of Biomedical Engineering, Johns Hopkins University
Yuxin Bai
Department of Biomedical Engineering, Johns Hopkins University
Yuxuan Wang
Sambit Panda
Department of Biomedical Engineering, Johns Hopkins University
Adam Li
Department of Computer Science, Columbia University
Haoyin Xu
Department of Biomedical Engineering, Johns Hopkins University
Eliza O’Reilly
Department of Applied Mathematics and Statistic, Johns Hopkins University
Lisa Dobbyn
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Maria Popoli
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Janine Ptak
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Natalie Silliman
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Chris Thoburn
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Jeanne Tie
Division of Personalized Oncology, Walter and Eliza Hall Institute of Medical Research
Peter Gibbs
Division of Personalized Oncology, Walter and Eliza Hall Institute of Medical Research
Lan T. Ho-Pham
BioMedical Research Center, Pham Ngoc Thach University of Medicine
Bich N. H. Tran
Saigon Precision Medicine Research Center
Thach S. Tran
Saigon Precision Medicine Research Center
Tuan V. Nguyen
Saigon Precision Medicine Research Center
Maximilian F. Konig
The Ludwig Center for Cancer Genetics and Therapeutics, Johns Hopkins University School of Medicine
Michelle Petri
Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine
Antony Rosen
Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine
Christopher A. Mecoli
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Ami A. Shah
Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine
Chetan Bettegowda
Kenneth W. Kinzler
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Nickolas Papadopoulos
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Joshua T. Vogelstein
Department of Biomedical Engineering, Johns Hopkins University
Bert Vogelstein
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Christopher Douville
Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Frederikus A. Klok
Jan Beyer-Westendorf
Luis Jara-Palomares
Walter Ageno
Mike J.L. Peters
Aurélien Delluc
Myron Best
Noori Guman
Hans-Martin Otten
Frits Mulder
Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam
Nick van Es
Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam