Fragmentation signatures in cancer patients resemble those of patients with vascular or autoimmune diseases
- PMID: 40833414
- PMCID: PMC12402995
- DOI: 10.1073/pnas.2426890122
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.
Keywords: autoimmune diseases; cancer screening; cell-free DNA; fragmentomics; rheumatology.
Conflict of interest statement
Competing interests statement:J.T. has a speaking, advisory, and consultancy with Haystack Oncology, Amgen, Novartis, AstraZeneca, Merck Serono, Merck Sharp & Dohme, Beigene, Pierre Fabre, Bristol Myers Squibb, Gilead, and Daiichi Sankyo. K.W.K., B.V., and N.P. are founders of Thrive Earlier Detection, an Exact Sciences Company. K.W.K., N.P., and C.D. are consultants to Thrive Earlier Detection. K.W.K. and N.P. are consultants to Neophore. K.W.K., B.V., N.P., and C.D. hold equity in Exact Sciences. K.W.K., B.V., and N.P. are founders of and own equity in Haystack Oncology & ManaT Bio. B.V. is a consultant to and holds equity in Catalio Capital Management. C.B. is a co-founder of OrisDx. C.B. and C.D. are co-founders of Belay Diagnostics. K.W.K., B.V., and N.P., hold equity in and are consultants to CAGE Pharma. The companies named above, as well as other companies, have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. C.B., K.W.K., N.P., B.V., and C.D., are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. Patent applications on the work described in this paper may be filed by Johns Hopkins University. The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies.
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