Reactive oxygen species (ROS) are known to induce DNA damage, including oxidized bases, the formation of DNA adducts and DNA strand breaks, which could lead to genomic instability and oncogenesis. The damaging effects of ROS could be countered by the antioxidant action of non-enzymatic antioxidants (including a variety of ROS quenchers such as vitamins, minerals [iron, zinc, copper, selenium, and manganese], thiols [including glutathione or GSH], uric acid, bilirubin, and flavonoids), or by endogenous antioxidant enzymes.

Superoxide dismutase (SOD) is one of the key enzymes involved in antioxidant function. It is responsible for converting the harmful superoxide radical (O₂^–) to hydrogen peroxide (H₂O₂), shielding the organism against its damaging effects. However, under certain circumstances, an increased MnSOD activity may lead to cell damage by H₂O₂ overproduction. It is thought that genetic polymorphisms in such an enzyme could lead to altered functionality and thus reduced ROS detoxification.

Among the endogenous antioxidants, SOD2 (or also called manganese superoxide dismutase, MnSOD) is the only one found within the mitochondria, which is a major site for ROS production. Most of the ROS generation occurs during the electron transport chain (ETC) in the mitochondria, where large amounts of O₂^– are formed from oxidative phosphorylation. After the alteration of O₂^– by SOD, antioxidant enzymes catalase (CAT) and glutathione peroxidase (GPx) utilise H₂O₂ as substrate to further convert and neutralise it to water (H₂O) and oxygen. The SOD2 enzyme possesses an active site that has manganese as transition metal for rapid electron exchange within the mitochondria.

The MnSOD gene, located on chromosome 6q25.3, consists of four introns and five exons. The MnSOD gene has been described as a tumour suppressor gene as it reduces oxidative stress and mitochondrial DNA damage that could play a significant role in carcinogen­esis. The MnSOD protein is synthesised in the cytoplasm, after which it is transported into the mitochondria to serve its essential antioxidative function. Although several polymorphisms have been identified (at least 190 SNPs in humans), rs4880 is most extensively studied.

Reports indicate that, in the Val-variant (T-allele), impaired co-translational import is observed, which causes for slower mitochondrial transportation, lower levels of the mature exogenous protein, lower SOD2 activity and decreased mRNA expression and stability than the Ala-variant. A previous study has also shown that the Ala-variant allowed for more efficient MnSOD localisation to the mitochondria than the Val-variant form; the Ala-variant precursor reportedly generates 30-40% more of the active, matrix-MnSOD in comparison with the Val-allele precursor. Considering these findings, the Val-allele of MnSOD may be associated with less enzymatic activity, higher levels of ROS and increased susceptibility to cancer.

On the other hand, if the Ala-variant of MnSOD is related to higher SOD2 activity, it could translate into a higher production of H₂O₂ and elevated metastatic activity in individuals unable to further neutralise such radicals. 

Although this SNP is said to seriously impact the function of SOD2, studies on the relation between the SOD2 rs4880 polymorphism and the development of various cancers seem conflicting. Several studies have found an association between the Val-allele and increased cancer risk (such as breast, lung and pancreatic cancer), although the majority of studies shows the Ala-variant to be associated with higher cancer risk such as breast, esophageal, colorectal, prostate and cervical cancer, while other studies however, find no significant associations.  

A recent 2018 meta-analysis from Wang et al. found the rs4880 SNP associated with an increased overall cancer risk. The subgroup analysis further indicated a specific risk only for prostate cancer and increased cancer risk in Caucasians. The authors have considered 88 studies with 33 098 cases and 37 831 controls to find no significant association between this polymorphism and breast cancer risk; this is consistent with many previous meta-analyses. In 2017, a meta-analysis from a different group of researchers also failed to find a signifi­cant relationship between the rs4880 polymorphism and breast cancer risk or survival, although in Caucasian patients, the TT genotype (Val/Val) may marginally decrease the risk of breast cancer in comparison to the CT + CC genotype (Ala-allele carriers). This meta‑analysis consisted of 18 481 cases and 19 527 controls from 27 cohorts or case‑control studies for risk analysis and 5 746 cancer patients from eight studies for survival analysis. 

Despite genetic importance, environmental factors such as dietary pattern and exercise have been found integral in the development of cancer. Different studies have analysed the combined effect of the MnSOD SNP with factors that may increase ROS production, such as smoking and alcohol intake. Several studies have also investigated the association between dietary intake of antioxidant-rich foods and the rs4880 polymorphism in breast cancer, prostate cancer and cervical cancer. Results suggest that the Ala16Val polymorphism and cancer risk could be modulated by dietary factors, although research remains somewhat conflicting.

Antioxidants

Generally, diets rich in fruits and vegetables are associated with lower risk of cancer, probably partially ascribed to the antioxidant properties of these foods. One of the earliest studies from Ambrosone et al. (1999) found that women homozygous for the Ala-allele and with a lower antioxidant intake, presented a higher risk for breast cancer development. On the other hand, women carrying the Ala-allele and consuming adequate dietary antioxidants such as fruits, vegetables, etc., were later found to be at a decreased risk for breast cancer.

Ambrosone et al. (1999) reported an association between premenopausal Ala-allele carriers who had a low antioxidant consumption (defined as an intake of fruit and vegetables as well as dietary ascorbic acid, α-tocopherols, and carotenoids below the median) and increased breast cancer risk. An association of the MnSOD Ala16Val SNP with plasma carotenoid concentrations has also been reported for prostate cancer risk and aggressiveness, with a significant higher risk from the combination of low antioxidant status and the homozygous Ala genotype.