Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer.

Ella Grilz,Lisa‐Marie Mauracher,Florian Posch,Oliver Königsbrügge,Irene Lang,Christine Marosi,Cihan Ay,Ingrid Pabinger,Sabine Zöchbauer‐Müller

doi:10.1111/bjh.15906

Ella Grilz, Lisa‐Marie Mauracher + Show 7 more

Open Access

https://doi.org/10.1111/bjh.15906

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Abstract

SummaryPrior studies indicate that neutrophil extracellular traps (NETs) are associated with arterial thromboembolism (ATE) and mortality. We investigated the association between NET formation biomarkers (citrullinated histone H3 [H3Cit], cell‐free DNA [cfDNA], and nucleosomes) and the risk of ATE and all‐cause mortality in patients with cancer. In this prospective cohort study, H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients with newly diagnosed cancer or progressive disease after remission were followed for 2 years for ATE and death. Nine‐hundred and fifty‐seven patients were included. The subdistribution hazard ratios for ATE of H3Cit, cfDNA and nucleosomes were 1·0 per 100 ng/ml increase (95% confidence interval [95% CI]: 0·7–1·4, P = 0·949), 1·0 per 100 ng/ml (0·9–1·2, P = 0·494) increase and 1·1 per 1‐unit increase (1·0–1·2, P = 0·233), respectively. Three‐hundred and seventy‐eight (39·5%) patients died. The hazard ratio (HR) for mortality of H3Cit and cfDNA per 100 ng/ml increase was 1·1 (1·0–1·1, P < 0·001) and 1·1 (1·0–1·1, P < 0·001), respectively. The HR for mortality of nucleosome levels per 1‐unit increase was 1·0 (1·0–1·1, P = 0·233). H3Cit, cfDNA and nucleosome levels were not associated with the risk of ATE in patients with cancer. Elevated H3Cit and cfDNA levels were associated with higher mortality in patients with cancer.

Highlights

The absolute neutrophil count (ANC) was weakly correlated with the levels of H3Cit, cell free DNA (cfDNA), and nucleosomes
H3Cit levels were highest in patients with prostate cancer, cfDNA levels were highest in patients with gastric cancer (419Á0 ng/ml; 292Á8–560Á7), and nucleosome levels were highest in patients with lymphoma (1Á9 MoM; 0Á9–3Á7)
Univariable analyses found no association between the risk of arterial thromboembolism (ATE) and H3Cit, cfDNA (SHR per 100 ng/ml increase = 1Á0, 0Á9–1Á2, P = 0Á494) and nucleosomes (SHR per unit increase = 1Á1, 1Á0–1Á2, P = 0Á233)

Summary

Methods

This study was conducted at the Vienna General Hospital of the Medial University of Vienna, within the framework of the Vienna Cancer and Thrombosis Study (CATS). All patients were followed for a maximum duration of 2 years, or until the occurrence of ATE, loss of follow-up, withdrawal of consent, or death. The primary endpoint of this analysis was death of any cause. ATE was the secondary endpoint, and was defined as a composite of myocardial infarction, ischaemic stroke, and peripheral arterial occlusion if an interventional procedure was conducted. A panel of experts in the field of cardiology, neurology and vascular medicine adjudicated all ATEs. More detailed information regarding the definition and adjudication ATE events have been reported previously (Grilz et al, 2018)

Results

Discussion

Conclusion