Folate and methionine are critical for one-carbon metabolism impacting DNA synthesis, repair, and methylation processes, as well as polyamine synthesis. These micronutrients have been implicated in colorectal cancer risk. There are, however, inconsistencies within the literature, with some studies showing restriction to have tumour-inhibitory effects, whereas others suggest excess to have adverse outcomes. We conducted a review of the published data to examine the accumulated evidence for involvement of dietary folate and/or methionine restriction or excess in intestinal tumour development in the Apc(Min/+) mouse model, which is genetically prone to develop such cancers. Thirteen publications were selected for evaluation based on the following inclusion criteria: (i) use of Apc(Min/+) mouse model; (ii) interventions using dietary folate and/or methionine; and (iii) primary outcome measures focused on intestinal tumour development. We found that nutritional modulation of folate and methionine was shown to have different effects on intestinal cancer in the Apc(Min/+) mouse, depending on the dosage, duration and timing of intervention, and interaction of the Apc(Min/+) genotype with other genetic factors affecting folate and DNA methylation metabolism. Although some studies showed that folate deficiency before tumorigenesis tended to increase risk of tumour formation, there are inconsistencies regarding whether excess folate post-weaning or after tumour initiation increases intestinal tumour burden. Altogether, the pooled data do not appear to indicate a difference in effect on intestinal tumour incidence between post-weaning diets that are folate deficient or folate adequate. The Apc(Min/+) mouse is a useful model for assessment of the impact of dietary folate on intestinal tumour development, but further research is required to understand the reasons for these inconsistencies amongst studies based on likely mechanisms, including modulation of nucleotide synthesis, DNA methylation, and chromosomal instability, which may affect the rate of cellular division and its control.
Micronucleus assay has been used as a biomarker of DNA damage, chromosomal instability, cancer risk and accelerated aging. In this review, a meta-analysis was performed to assess the association between micronuclei (MNi) and diseases with increased advanced glycation end products (AGEs) and HbA1c. The review identified eight studies with 632 subjects with disease and 547 controls. The Mean Ratio (MRi) for AGE levels (MRi = 2.92, 95 %CI: 2.06-4.13, P < 0.00001) and HbA1c levels (MRi = 1.32, 95 %CI: 1.12-1.56, P = 0.001) were significantly higher in the disease group compared to healthy controls. The meta-analysis indicated that the overall estimates of MRi for MNi was 1.83 (95 %CI: 1.38-2.42, p < 0.0001) in subjects with disease compared to controls. Significant increases in MRi for MNi were also observed in the following sub-groups: subjects with disease for elevated AGEs (MRi = 1.62, 95 %CI: 1.12-2.35, P = 0.01), elevated HbA1c (MRi = 2.13, 95 %CI: 1.33-3.39, P = 0.002), lymphocytes MNi (MRi = 1.74, 95 %CI: 1.29-2.33, P = 0.0003), exfoliated buccal cells MNi (MRi = 2.86, 95 %CI: 1.19-6.87, P = 0.02), type 2 diabetes mellitus (T2DM) (MRi = 1.99, 95 %CI: 1.17-3.39, P = 0.01), chronic renal disease (MRi = 1.68, 95 %CI: 1.18-2.38, P = 0.004) and other disease groups (MRi = 2.52, 95 %CI: 1.28-4.96, P = 0.008). The results of this review suggest that MNi could be used as a biomarker of DNA damage and chromosomal instability in degenerative disease where increased AGEs and HbA1c are implicated. The lack of heterogeneity for MN frequency when considered either for all studies or subgroup strengthened the MRi of the meta-analysis. However, the lack of significant association between MRi for MNi and MRi for AGEs or HbA1c indicates that the case-control studies investigated may be confounded by other variables. Thus, larger studies with long term AGE exposure is warranted to further understand the role of MN formation in the initiation and progression of diseases caused by excessive glycation.
The purpose of the "Micronuclei and Disease" special issue (SI) is to: (i) Determine the level of evidence for association of micronuclei (MN), a biomarker of numerical and structural chromosomal aberrations, with risk of specific diseases in humans; (ii) Define plausible mechanisms that explain association of MN with each disease; (iii) Identify knowledge gaps and research needed to translate MN assays into clinical practice. The "MN and Disease" SI includes 14 papers. The first is a review of mechanisms of MN formation and their consequences in humans. 11 papers are systematic reviews and/or meta-analyses of the association of MN with reproduction, child health, inflammation, auto-immune disease, glycation, metabolic diseases, chronic kidney disease, cardiovascular disease, eleven common cancers, ageing and frailty. The penultimate paper focuses on effect of interventions on MN frequency in the elderly. A road map for translation of MN data into clinical practice is the topic of the final paper. The majority of reviewed studies were case-control studies in which the ratio of mean MN frequency in disease cases relative to controls, i.e. the mean ratio (MR), was calculated. The mean of these MR values, estimated by meta-analyses, for lymphocyte and buccal cell MN in non-cancer diseases were 2.3 and 3.6 respectively, and for cancers they were 1.7 and 2.6 respectively. The highest MR values were observed in studies of cancer cases in which MN were measured in the same tissue as the tumour (MR = 4.9-10.8). This special issue is an important milestone in the evidence supporting MN as a reliable genomic biomarker of developmental and degenerative disease risk. These advances, together with results from prospective cohort studies, are helping to identify diseases in which MN assays can be practically employed in the clinical setting to better identify high risk patients and to prioritise them for preventive therapy.
As human life expectancy increases substantially and aging is the primary risk factor for most chronic diseases, there is an urgent need for advancing the development of post-genomic era biomarkers that can be used for disease prediction and early detection (DPED). Mosaic loss of Y chromosome (LOY) is the state of nullisomy Y in sub-groups of somatic cells acquired from different post-zygotic development stages and onwards throughout the lifespan. Multiple large-cohort based epidemiology studies have found that LOY in blood cells is a significant risk factor for future mortality and various diseases in males. Many features intrinsic to LOY analysis may be leveraged to enhance its use as a non-invasive, sensitive, reliable, high throughput-biomarker for DPED. Here, we review the emerging literatures in LOY studies and highlight ten strengths for using LOY as a novel biomarker for genomics-driven DPED diagnostics. Meanwhile, the current limitations in this area are also discussed. We conclude by identifying some important knowledge gaps regarding the consequences of malsegregation of the Y chromosome and propose further steps that are required before clinical implementation of LOY. Taken together, we think that LOY has substantial potential as a biomarker for DPED, despite some hurdles that still need to be addressed before its integration into healthcare becomes acceptable.
According to the definition delivred by the WHO, a biomarker, independently from its role that may be indicative of exposure, response or effect, is inevitably linked to a clinical outcome or to a disease. The presence of a continuum from early biological events to therapy, and prognosis is the unifying mechanism that justifies this conclusion. Traditionally, the technical and inter-individual variability of the assays, together with the long duration between early pathogenetic events and the disease, prevented clinical applications to these biomarkers. These limitations became less important with the emerging of personalized preventive medicine because of the focus on disease prediction and prevention, and the recommended use of all data concerning measurable patient's features. Several papers have been published on the best validation procedures for translating biomarkers to real life. The history of cholesterol concentration is extensively discussed as a reliable example of a biomarker that - after a long and controversial validation process - is currently used in clinical practice. The frequency of micronucleated cells is a reliable biomarker for the pathogenesis of cancer and other non-communicable diseases, and the link with clinical outcomes is substantiated by epidemiological evidence and strong mechanistic basis. Available literature concerning the use of the micronucleus assay in clinical studies is discussed, and a suitable three-levels road-map driving this biomarker towards clinical practice is presented. Under the perspective of personalized medicine, the use of the micronucleus assays can play a decisive role in addressing preventive and therapeutic strategies of chronic diseases. In many cases the MN assay is either currently used in clinical practice or classified as adequate to consider translation into practice. The roadmap to clinical validation of the micronucleus assay finds inspiration from the history of biomarkers such as cholesterol, which clearly showed that the evidence from prospective studies or RCTs is critical to achieve the required level of trust from the healthcare profession. (307 words).
In this review we bring together evidence that (i) RNA viruses are a cause of chromosomal instability and micronuclei (MN), (ii) those individuals with high levels of lymphocyte MN have a weakened immune response and are more susceptible to RNA virus infection and (iii) both RNA virus infection and MN formation can induce inflammatory cytokine production. Based on these observations we propose a hypothesis that those who harbor elevated frequencies of MN within their cells are more prone to RNA virus infection and are more likely, through combined effects of leakage of self-DNA from MN and RNA from viruses, to escalate pro-inflammatory cytokine production via the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) and the Senescence Associated Secretory Phenotype (SASP) mechanisms to an extent that is unresolvable and therefore confers high risk of causing tissue damage by an excessive and overtly toxic immune response. The corollaries from this hypothesis are (i) those with abnormally high MN frequency are more prone to infection by RNA viruses; (ii) the extent of cytokine production and pro-inflammatory response to infection by RNA viruses is enhanced and possibly exceeds threshold levels that may be unresolvable in those with elevated MN levels in affected organs; (iii) reduction of MN frequency by improving nutrition and life-style factors increases resistance to RNA virus infection and moderates inflammatory cytokine production to a level that is immunologically efficacious and survivable.
Micronucleus (MN) assay has been widely used as a biomarker of DNA damage, chromosomal instability, cancer risk and accelerated aging in many epidemiological studies. In this narrative review and meta-analysis we assessed the association between lymphocyte micronuclei (MNi) and cancers of the skin, blood, digestive tract, and prostate. The review identified nineteen studies with 717 disease subjects and 782 controls. Significant increases in MRi for MNi were observed in the following groups: subjects with blood cancer (MRi = 3.98; 95 % CI: 1.98-7.99; p = 0.000) and colorectal cancer (excluding IBD) (MRi = 2.69; 95 % CI: 1.82-3.98, p