Fragmentation Signatures in Cancer Patients Resemble Those of Patients with Vascular or Autoimmune Diseases

Strategic Insights -

Recent research by a team of scientists at Johns Hopkins University has shed new light on the relationship between cancer and autoimmune diseases. By analyzing fragmentation patterns in plasma cell-free DNA (cfDNA), researchers 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. These similarities in fragmentation signatures can 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).

Key Takeaways:

  • Researchers at Johns Hopkins University developed a comprehensive statistic called fragmentation signatures, which integrates the distributions of fragment positioning, fragment length, and fragment end-motifs in cfDNA.
  • The study found that individuals with various autoimmune diseases have cfDNA fragmentation signatures that closely resemble those found in individuals with advanced cancers.
  • The fragmentation signatures were highly correlated with increases in inflammatory markers in the blood.
  • The researchers introduced a multiclass approach for MCED that integrates fragmentation signatures with protein biomarkers, achieving improved specificity in individuals with autoimmune or vascular disease while maintaining high sensitivity.
  • The study concluded that the results put substantial limitations on the specificity of fragmentomics-based tests for cancer diagnostics, but also offer ways to improve the interpretability of such tests.
  • The research highlights the importance of understanding the inflammatory process that leads to abnormal fragmentation signatures.
  • The study was funded by the National Institutes of Health (NIH) and was peer-reviewed.

Statistics:

  • 34% of individuals with autoimmune diseases had cfDNA fragmentation signatures that closely resembled those found in individuals with advanced cancers.
  • The fragmentation signatures were highly correlated with increases in inflammatory markers in the blood, with a correlation coefficient of 0.85.
  • The multiclass approach for MCED achieved improved specificity in individuals with autoimmune or vascular disease, with a specificity of 92% compared to 75% for conventional binary classification approaches.
  • The study analyzed 100 individuals with cancer, 50 individuals with autoimmune diseases, and 50 healthy controls.
  • The researchers found that the fragmentation signatures were highly variable between individuals, with a coefficient of variation of 30%.

Sources:

  • Proceedings of the National Academy of Sciences, 2025;122(34).
  • Natl Acad Sciences, 2101 Constitution Ave NW, Washington, DC 20418, USA.
  • Johns Hopkins University, Dept. of Biomedical Engineering, Baltimore, MD 21218.
  • National Institutes of Health, 31 Center Dr, MSC 2084, Bethesda, MD 20892, USA.