DNA damage and repair in colorectal cancer patients : Long-term host response and dietary intervention after curative treatment

Abstract

Colorectal cancer (CRC) is the third most common cancer worldwide, with Norway ranking among the highest in incidence rate. Treatment strategies include surgical removal of the tumour, and frequently chemotherapy and radiotherapy (rectal carcinoma), primarily determined by tumour location and staging. Currently, the standard approach for staging colorectal tumours is the tumournode-metastasis (TNM) system. Advancement in early detection and treatment strategies have resulted in a growing population of CRC survivors. This population is not only at risk for recurrent disease but also at an increased risk of secondary cancers and comorbidities.

Accumulation of DNA damage is a critical feature in genomic instability, which is a hallmark of various cancers, including CRC. The pathogenesis of CRC is a complex multistep process in which oxidative stress and inflammation are central underlying disease mechanisms. DNA damage caused by oxidative stress plays a key role in the carcinogenesis. However, dietary factors strongly influence DNA integrity, with numerous bioactive compounds found in plant foods having the potential to dampen oxidative stress and inflammation, thus protecting DNA from oxidative damage.

In human biomonitoring, the comet assay (single-cell gel electrophoresis) is a widely used method to assess DNA damage and DNA repair in peripheral blood mononuclear cells (PBMCs). The Norwegian Dietary Guidelines and Colorectal Cancer Survival (CRC-NORDIET) study is a randomized controlled trial (RCT) designed to investigate the effect of a dietary intervention on disease outcome and survival in CRC patients. The overall aim of this thesis (sub-project within the CRC-NORDIET) was to investigate the long-term host response and the effect of a dietary intervention and after curative treatment, utilizing the comet assay. The intervention group received an intensive personalized dietary intervention, including a prudent diet in accordance with the Norwegian food-based dietary guidelines (NFBDGs), emphasizing specific antioxidant-rich and anti-inflammatory foods and drinks.

In Paper I, using samples from the post-surgery baseline visit, we observed that patients diagnosed with regional disease (stage III) had a higher level of DNA base oxidation compared with those with localized disease (stage I-II). In patients exposed to chemotherapy, DNA base oxidation was negatively associated with number of days since last dosage. Additionally, both high absolute and relative amounts of fat tissue, as well sedentary behaviour, were positively associated with DNA base oxidation in the chemotherapy group. In Paper II, we found a reduction in DNA base oxidation after one-year personalized dietary intervention in post-surgery CRC patients. In Paper III, where we investigated whether dietary factors could affect DNA repair, no effect was observed after a 6 months dietary intervention. In Paper IV, as a follow-up to Paper I, we revealed that the initial elevated levels of DNA base oxidation observed in CRC patients diagnosed with regional disease, subsequently decreased to levels comparable to patients with localized disease after 6 and 12 months.

In conclusion, the findings in this thesis demonstrate that DNA base oxidation varies according to tumour and lifestyle related factors in CRC patients treated for non-metastatic disease. Further, adherence to a prudent diet, which includes foods and drinks known to dampen oxidative stress and inflammation, may serve as a potential moderator for DNA protection against oxidation damage. Our findings do not support that dietary factors impacts DNA repair activity during the first 6 months of a personalized intensive dietary intervention.