Pilot Study on Malnutrition and DNA Damage in Patients with Newly Diagnosed Gastrointestinal Tumors: Is DNA Damage Reversible by Early Individualized Nutritional Support?

BACKGROUND AND AIMS: Nutritional support (NS) in patients with malignancies and malnutrition improves outcome and treatment tolerance. The underlying mechanisms are not completely understood. We aimed to investigate for the first time the influence of an early individualized NS in newly diagnosed patients with gastrointestinal/hepato-pancreatic malignancies and malnutrition on DNA damage, oxidative stress and subclinical inflammation. METHODS: This prospective case-control study included 43 patients with newly diagnosed malignancies and malnutrition. At baseline (F0), we documented patients' data, oncological diagnosis, comorbidities, alcohol/ nicotine consume. Nutritional parameters, DNA damage [histone-variant H2AX phosphorylated on the 139-serine residue (γ-H2AX) foci/cell], oxidative status, subclinical inflammation were measured. During diagnostic workup, patients received an individualized NS, and got a follow-up before the start of treatment (F1), (n=21). Healthy controls (n=21) were included for comparison of DNA damage at baseline. RESULTS: γ-H2AX-values at baseline were higher than in controls (p<0.001) and higher than after the NS at F1 (p=0.011). Patients with severe gastrointestinal symptoms (SGS) had higher baseline foci compared to patients with mild gastrointestinal symptoms (MGS) at F0 (p<0.001) and showed a stronger decrease of DNA damage under NS (p=0.002). Laboratory data were stable, with tendential reduction in oxidative stress, without progression of subclinical inflammation. The number of γ-H2AX foci did not differ among patients divided by sex, age, nicotine or alcohol intake or the presence of distant metastases. CONCLUSION: Increased baseline DNA damage in patients with newly diagnosed tumors and malnutrition decreased under pretherapeutic NS, independent of other known genotoxic factors. This contributes towards understanding the positive effects of early NS in cancer management.

DNA damage in lymphocytes of patients suffering from complex traumatization.

It has been shown that complex childhood traumatization (CCT) increases the risk for severe somatic and mental disorders. However, the somatic pathways linking maladaptive affect regulation and disease are not understood. Here we tested the hypothesis that traumatic stress is linked to the induction of DNA damage. We isolated peripheral lymphocytes (PBLCs) from blood of healthy donors and patients suffering from CCT. Cells were immobilised on slides and stained with anti-phosphohistone 2AX (γH2AX). The number of γH2AX foci, which are an accepted surrogate marker of DNA double-strand breaks (DSBs), was determined and set in relation to the patient characteristics. We show that CCT patients (HS) have higher levels of DSBs in PBLCs than healthy volunteers (CG) and psychiatric patients without CCT (LS) (HS: 0.88±0.46 foci/cell; LS: 0.31±0.23 foci/cell; CG: 0.15±0.10 foci/cell). The difference between HS and control group was highly significant (p<0.001). Insecure-dismissing attachment as a psychological marker was related to an increase in the γH2AX foci in all groups, but especially in the CCT patients. There was no significant correlation in the γH2AX level to potential external genotoxic influences such as smoking and alcohol consumption. In PBLCs, spontaneous occurring γH2AX foci partially colocalized with 53BP1 and pATM, supporting the notion they represent DSBs. Overall, our data indicate that complex traumatization is a source of genotoxic stress that can cause systemic DNA damage, pointing to the importance of emotional early life experiences for the genetically determined health status in later life periods. The finding of CCT to be interrelated to genomic instability opens new opportunities for a deeper understanding of the link between emotional stress, DNA damage and somatic disorders.