Histone-based liquid biopsy discriminates between myelodysplastic syndrome and solid malignancies

Background: Cancers can be hematological or solid, sharing many hallmarks, although their clinical behaviors are distinct. Identifying biomarkers that differentiate hematological from non-hematological malignancies could aid differential diagnosis by providing the basis for developing point-of-care diagnostic devices. In this respect, complex histone populations are secreted and detectable in biological fluids in various disease settings. To our knowledge, studies analyzing the circulating histone profile complexity by comparing healthy individuals, patients with hematological malignancies, and solid cancer patients are currently lacking. Results: We assessed the plasma histone signature of healthy subjects (n = 30), and of patients with myelodysplastic syndrome (MDS, n = 43), colorectal cancer (CRC, n = 39), lung cancer (non-small cell lung cancer [NSCLC, n = 15]), small cell lung cancer [SCLC, n = 4]), or breast cancer [BC, n = 16]). Principal component analysis (PCA) demonstrated the segregation of circulating histones and histone complexes between oncological and healthy patients. Individual histones (H2A, H2B, H3, H4, macroH2A1.1, and macroH2A1.2), histone dimers and nucleosomes were assayed by ImageStream(X)-advanced flow cytometry. We found general increases in circulating histone abundance in the blood of cancer patients versus healthy controls. MDS and solid cancers could be discriminated among themselves for an increased abundance of histones H2A and macroH2A1.2 (p < 0.01), and a decreased abundance of H2A/H2B/H3/H4 and H3/H4 histone complexes (p < 0.01). Moreover, macroH2A1.2 and H2A/H2B/H3/H4 levels negatively or positively correlated with age in healthy subjects versus MDS patients, respectively. Conclusions: Overall, we identified circulating histone signatures able to discriminate between solid and MDS, using a rapid and non-invasive imaging technology, which may improve patient diagnosis.