Liquid biopsies have emerged as a minimally invasive cancer detection and monitoring method, which could identify cancer-related alterations in nucleosome or histone levels and modifications in blood, saliva, and urine. Histones, the core component of the nucleosome, are essential for chromatin compaction and gene expression modulation. Increasing evidence suggests that circulating histones and histone complexes, originating from cell death or immune cell activation, could act as promising biomarkers for cancer detection and management. In this review, we provide an overview of circulating histones as a powerful liquid biopsy approach and methods for their detection. We highlight current knowledge on circulating histones in hematologic malignancies and solid cancer, with a focus on their role in cancer dissemination, monitoring, and tumorigenesis. Last, we describe recently developed strategies to identify cancer tissue-of-origin in blood plasma based on nucleosome positioning, inferred from nucleosomal DNA fragmentation footprint, which is independent of the genetic landscape.

Introduction: The most common liver disease is nonalcoholic fatty liver disease, characterized by an intrahepatic accumulation of lipids that most often accompanies obesity. Fatty liver can evolve, in the presence of oxidative stress and inflammation, into disabling and deadly liver diseases such as cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma (CC). Old age seems to favor HCC and CC, in agreement with the inflammaging theory, according to which aging accrues inflammation. Cancer, in general, is an age-related disease, as incidence and mortality for most types of cancer increase with age. However, how molecular drivers in tumors differ or are mutated more frequently among patients of different ages remains scarcely investigated. A recent integrative analysis of the age-associated multi-omic landscape across cancers and healthy tissues demonstrated that age-related gene expression changes are linked to numerous biological processes. HCC and CC have among the lowest five-year survival estimates due to their aggressive progression. Materials and methods: In this study, we extracted top gene candidates from the above-mentioned pan-analyses (i.e., B2M, C1qA, SUCLG1) and tested by qPCR their expression and their correlation with disease progression in 48 tissue samples covering liver disease stages (fatty liver, hepatitis, cirrhosis, HCC and CC) and normal tissues. Results: Here, we report a significant downregulation in the expression of the age-associated gene SUCLG1 during the progression of liver disease toward HCC and CC, which also associates with poor patient survival. Conclusion: SUCGL1, a mitochondrial enzyme gene that catalyzes the conversion of succinyl CoA to succinate, might be therapeutically targeted for the development and progression of age-associated liver cancers with low survival rates.

Circulating histones are increasingly recognised as biologically relevant components of extracellular chromatin, but their composition and treatment-associated dynamics in acute myeloid leukaemia (AML) remain poorly defined. In this prospective single-centre observational study, we profiled 13 histone measures by ImageStream imaging flow cy-tometry in 31 plasma samples from 15 newly diagnosed AML patients at diagnosis/day 7/day 28 (n=15/10/6), with 30 healthy controls and 12 patients with myelodysplastic neoplasms with increased blasts. At diagnosis, nine of 13 measures differed from controls after false discovery rate (FDR) correction, defining a bidirectional profile with higher H2A-, H2B- and macroH2A1-associated measures and lower H3, H4 and H3/H4; the largest differences included in-creased macroH2A1.1 (7.07% vs. 0.47%; δ=0.98) and reduced H4 (0.14% vs. 3.25%; δ=−0.87). By day 7, five measures remained FDR-significant, all decreasing: H4, H3/H4 and the three tetrameric complexes. At day 28, no paired comparison remained FDR-significant; however, H3/H4 showed a significant overall temporal change across the six complete serial trajectories (q = 0.0334). Exploratory day-28 trajectories showed concordant decreases in all three tetrameric complexes in complete remission, with opposite changes in residual disease. MDS with increased blasts showed higher macroH2A1-containing tetrameric complexes than controls and AML. These findings support disease- and treatment-associated redistribution of circulating histone populations across myeloid neoplasia.