Lymphocyte Micronucleus Formation Is Driven by Inflammation-Induced Oxidative DNA Damage in Oesophageal Cancer Development.

We investigated mechanisms underlying circulating DNA damage across the gastro-oesophageal reflux disease (GORD), Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC) spectrum using the lymphocyte micronucleus (MN) assay. MN frequency (MN%) was quantified in lymphocytes from healthy volunteers (HVs), GORD, BO and OAC patients, alongside plasma biomarkers of inflammation and oxidative stress. Ex vivo challenge assays assessed lymphocyte responses to hydrogen peroxide (H2O2), vinblastine and the bile acid deoxycholic acid (DCA). Tissue-based NF-κB expression was also correlated with MN levels. OAC patients exhibited significantly elevated MN% compared with HVs (p < 0.001), GORD (p < 0.001) and BO (p = 0.016). OAC lymphocytes showed increased sensitivity to vinblastine relative to HVs (p = 0.025) and GORD patients (p = 0.033). Higher baseline MN% correlated with reduced inducible MN formation following H2O2 or DCA, suggesting altered oxidative stress responses. MN% also associated with plasma 8-OHdG, IL-8 and 2'3'-cGAMP, and with reduced oesophageal tissue IκB, indicating activation of oxidative and cGAS-STING/NF-κB signalling. These findings highlight systemic aneugenic and oxidative stress processes that contribute to lymphocyte MN formation in OAC and suggest that MN% may serve as a minimally invasive indicator of inflammation-linked genomic instability. Further investigation is needed to determine its relevance to OAC progression.