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Medical and Dietary Uses of N-Acetylcysteine.
Šalamon, Š, Kramar, B, Marolt, TP, Poljšak, B, Milisav, I
Antioxidants (Basel, Switzerland). 2019;8(5)
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N-Acetylcysteine (NAC) is an antioxidant naturally found in plants of the Allium species such as onions. As well as having antioxidant and anti-inflammatory properties, it is also needed to make glutathione which is an important antioxidant in cells. NAC has been used as a drug since the 1960s and is a popular dietary supplement. NAC is considered safe but the results of clinical trials are controversial or incomplete. This aim of this review is to provide a balanced view of further uses of NAC as a dietary supplement. It discusses the antioxidant properties in relation to conditions such as heart disease, diabetes and ageing; its medical uses, in the complementary treatment of cancer, as a sports supplement and as an anti-aging supplement. More information is needed on NAC and further clinical trials looking at its use in neurodegenerative diseases, addiction, and mental health disorders are underway. This may be relevant to the supplement users and may also help people suffering from chronic degenerative conditions.
Abstract
N-acetylcysteine (NAC), a plant antioxidant naturally found in onion, is a precursor to glutathione. It has been used as a drug since the 1960s and is listed on the World Health Organization (WHO) Model List of Essential Medicines as an antidote in poisonings. There are numerous other uses or proposed uses in medicine that are still in preclinical and clinical investigations. NAC is also used in food supplements and cosmetics. Despite its abundant use, there are projections that the NAC global market will grow in the next five years; therefore, the purpose of this work is to provide a balanced view of further uses of NAC as a dietary supplement. Although NAC is considered a safe substance, the results among clinical trials are sometimes controversial or incomplete, like for many other antioxidants. More clinical trials are underway that will improve our understanding of NAC applicability.
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Sorting out the Value of Cruciferous Sprouts as Sources of Bioactive Compounds for Nutrition and Health.
Abellán, Á, Domínguez-Perles, R, Moreno, DA, García-Viguera, C
Nutrients. 2019;11(2)
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Vegetable sprouts are naturally rich in nutrients and other beneficial compounds. The sprouts of cruciferous vegetables, such as broccoli, kale, radish and pak choi, stand out due to their high contents of glucosinolates and phenolic compounds. The aim of this review was to compile and update the available knowledge on the production, nutritional composition, and health benefits of cruciferous sprouts. A number of studies have found that compounds found in cruciferous sprouts have anti-cancer, anti-inflammatory, and antioxidant capacities. Consumption of cruciferous sprouts contributes to healthy glucose, insulin and fat levels in the blood, and may be beneficial for the treatment of some metabolic disorders, such as type 2 diabetes. There is evidence that compounds in cruciferous sprouts are a useful tool for enhancing phase II enzymes in the liver, and benefit levels of interleukine-6, C-reactive protein, and tumour necrosis factor-α, and inhibition of NF-κB, among others. The active compounds in these sprouts have an influence on several cardiovascular processes, potentially reducing the risk of several diseases. The lack of consistency between studies with regard to sampling schedules, doses, sample size, etc. means that it is not possible at this time to state the effective dose of sprouts or their active compounds needed in order to achieve health benefits. Further research is needed in this area.
Abstract
Edible sprouts with germinating seeds of a few days of age are naturally rich in nutrients and other bioactive compounds. Among them, the cruciferous (Brassicaceae) sprouts stand out due to their high contents of glucosinolates (GLSs) and phenolic compounds. In order to obtain sprouts enriched in these phytochemicals, elicitation is being increasing used as a sustainable practice. Besides, the evidence regarding the bioavailability and the biological activity of these compounds after their dietary intake has also attracted growing interest in recent years, supporting the intake of the natural food instead of enriched ingredients or extracts. Also, there is a growing interest regarding their uses, consumption, and applications for health and wellbeing, in different industrial sectors. In this context, the present review aims to compile and update the available knowledge on the fundamental aspects of production, enrichment in composition, and the benefits upon consumption of diverse edible cruciferous sprouts, which are sources of phenolic compounds and glucosinolates, as well as the evidence on their biological actions in diverse pathophysiological situations and the molecular pathways involved.
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The Effect of Nutrition Intervention with Oral Nutritional Supplements on Pancreatic and Bile Duct Cancer Patients Undergoing Chemotherapy.
Kim, SH, Lee, SM, Jeung, HC, Lee, IJ, Park, JS, Song, M, Lee, DK, Lee, SM
Nutrients. 2019;11(5)
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Despite the advantages of chemotherapy, it can cause cancer-related malnutrition leading to both reduced quality of life and reduced survival rate. Oral nutritional supplements (ONSs) provide balanced nutrients, calories, and protein to complement insufficient oral intake, and ONS provision during treatment may improve nutritional status. The aim of this study was to investigate the impact of ONS on nutritional status in patients undergoing chemotherapy for pancreatic and bile duct cancer. Patients were randomly allocated to the ONS group (15) and non-ONS group (19) and dietary intake and body weight were assessed at weeks 1, 2, 4 and 8. Body composition and quality of life was assessed at baseline and week 8. This study found the supply of ONS helped promote health by increasing body fat mass, improving quality of life and decreasing fatigue symptoms in pancreatic and bile duct cancer patients. These results were more pronounced in patients in the first cycle of chemotherapy. Based on these results, the authors conclude ONS may improve nutritional status by increasing fat mass and/or maintaining the body composition of patients undergoing chemotherapy.
Abstract
Chemotherapy may negatively affect nutritional status and quality of life (QOL) in pancreatic cancer patients. Our aim was to investigate the beneficial effects of oral nutrition supplements (ONS) on pancreatic and bile duct cancer patients undergoing chemotherapy. Among patients with progressive pancreatic and bile duct cancer receiving chemotherapy, the ONS group (n = 15) received two packs of ONS daily for 8 weeks while the non-ONS group (n = 19) did not. Anthropometric measures, dietary intake, nutritional status, and quality of life were assessed. ONS significantly increased daily intakes of energy, carbohydrates, proteins, and lipids at 8 weeks compared to the baseline. After 8 weeks, fat mass significantly increased in the ONS group. For patients in their first cycle of chemotherapy, body weight, fat-free mass, skeletal muscle mass, body cell mass, and fat mass increased in the ONS group but decreased in the non-ONS group. Fat mass increased in second or higher cycle only in the ONS group. Patient-generated subjective global assessments (PG-SGA) and fatigue scores in the Quality of Life Questionnaire Core 30 (QLQ-C30) improved in the ONS group. ONS might improve nutritional status by increasing fat mass and/or maintaining the body composition of pancreatic and bile duct cancer patients with chemotherapy, especially those in the first cycle, and alleviate fatigue symptoms.
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Association of Folate and Vitamins Involved in the 1-Carbon Cycle with Polymorphisms in the Methylenetetrahydrofolate Reductase Gene (MTHFR) and Global DNA Methylation in Patients with Colorectal Cancer.
Ferrari, A, Torrezan, GT, Carraro, DM, Aguiar Junior, S
Nutrients. 2019;11(6)
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This 2012 cross-sectional observational study examines the role of epigenetic gene expression and methylation in 189 patients with colorectal adenocarcinoma, including 128 with MTHFR polymorphisms. The mean age was 61 years and there was a 50/50 gender split. The focus nutrients were folate, vitamins B2, B6, B12, choline, betaine, and methionine, all of which are known to be essential nutrients for DNA synthesis and more specifically have a key role in the 1-carbon cycle, and S-adenosylmethionine (SAM). The study is based on prospective data collection from food frequency and clinical evaluation questionnaires, and blood work. There does not appear to have been any control group or blinding of processes (at least not reported in the study). The results showed that serum folate levels were positively correlated with the equivalent total dietary folate intake and global DNA methylation. No significant differences were found between serum folate levels in relation to the different genotypes of MTHFR polymorphisms such as C677T. A weak association was found between the A1298C polymorphism and lower levels of methylation. No significant findings were reported for the vitamins used in the study. The study concludes that folate intake, serum folate levels, global DNA methylation and age were predictors of clinicopathological staging.
Abstract
Folate, vitamin B2, vitamin B6, vitamin B12, choline, and betaine are nutrients involved in the 1-carbon cycle that can alter the levels of DNA methylation and influence genesis and/or tumor progression. Thus, the objective of this study was to evaluate the association of folate and vitamins involved in the 1-carbon cycle and MTHFR polymorphisms in global DNA methylation in patients with colorectal cancer gene. The study included 189 patients with colorectal adenocarcinoma answering a clinical evaluation questionnaire and the Food Frequency Questionnaire (FFQ) validated for patients with colon and rectal cancer. Blood samples were collected for evaluation of MTHFR gene polymorphisms in global DNA methylation in blood and in tumor. The values for serum folate were positively correlated with the equivalent total dietary folate (total DFE) (rho = 0.51, p = 0.03) and global DNA methylation (rho = 0.20, p = 0.03). Individuals aged over 61 years (p = 0.01) in clinicopathological staging III and IV (p = 0.01) and with + heterozygous mutated homozygous genotypes for the MTHFR A1298C gene had higher levels of global DNA methylation (p = 0.04). The association between dietary intake of folate, serum folate, and tumor stage were predictive of global DNA methylation in patients' blood. The levels of serum folate, the dietary folate and the status of DNA methylation can influence clinicopathological staging.
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Association of Frequency of Organic Food Consumption With Cancer Risk: Findings From the NutriNet-Santé Prospective Cohort Study.
Baudry, J, Assmann, KE, Touvier, M, Allès, B, Seconda, L, Latino-Martel, P, Ezzedine, K, Galan, P, Hercberg, S, Lairon, D, et al
JAMA internal medicine. 2018;178(12):1597-1606
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Cancer has several risk factors for its development including the presence of pesticides in the environment. Organic foods arguably have less pesticides than conventionally grown produce and the consumption of these should therefore lower an individuals chance of developing cancer. However, very few studies exist looking at this association. This observational study of 68946 individuals aimed to determine the association between organic food intake and cancer risk. The results showed that the most prevalent cancers were breast, prostate and skin cancer and an increased consumption of organic food, lowered the risk for the development of cancer. It was concluded that a higher intake of organic foods could reduce the risk of developing cancer, however further studies are warranted to investigate initial findings. This study could be used by healthcare professionals to understand that a diet rich in organic food could be of benefit for the prevention of cancer, however further studies are required before firm recommendations can be made.
Abstract
Importance: Although organic foods are less likely to contain pesticide residues than conventional foods, few studies have examined the association of organic food consumption with cancer risk. Objective: To prospectively investigate the association between organic food consumption and the risk of cancer in a large cohort of French adults. Design, Setting, and Participants: In this population-based prospective cohort study among French adult volunteers, data were included from participants with available information on organic food consumption frequency and dietary intake. For 16 products, participants reported their consumption frequency of labeled organic foods (never, occasionally, or most of the time). An organic food score was then computed (range, 0-32 points). The follow-up dates were May 10, 2009, to November 30, 2016. Main Outcomes and Measures: This study estimated the risk of cancer in association with the organic food score (modeled as quartiles) using Cox proportional hazards regression models adjusted for potential cancer risk factors. Results: Among 68 946 participants (78.0% female; mean [SD] age at baseline, 44.2 [14.5] years), 1340 first incident cancer cases were identified during follow-up, with the most prevalent being 459 breast cancers, 180 prostate cancers, 135 skin cancers, 99 colorectal cancers, 47 non-Hodgkin lymphomas, and 15 other lymphomas. High organic food scores were inversely associated with the overall risk of cancer (hazard ratio for quartile 4 vs quartile 1, 0.75; 95% CI, 0.63-0.88; P for trend = .001; absolute risk reduction, 0.6%; hazard ratio for a 5-point increase, 0.92; 95% CI, 0.88-0.96). Conclusions and Relevance: A higher frequency of organic food consumption was associated with a reduced risk of cancer. If these findings are confirmed, further research is necessary to determine the underlying factors involved in this association.
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Consumption of ultra-processed foods and cancer risk: results from NutriNet-Santé prospective cohort.
Fiolet, T, Srour, B, Sellem, L, Kesse-Guyot, E, Allès, B, Méjean, C, Deschasaux, M, Fassier, P, Latino-Martel, P, Beslay, M, et al
BMJ (Clinical research ed.). 2018;360:k322
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Foods that are heavily processed tend to have high levels of total fat, sugar and salt and low levels of fibre and vitamins. They also tend to have high levels of contaminants (caused for example by high heat treatment), food additives and plastic packaging exposure. This large prospective population-based cohort study assessed the association between ultra-processed food consumption and the incidence of cancer. The study found that ultra-processed food intake was associated with a higher overall cancer risk and a higher breast cancer risk. A 10% increase in the consumption of ultra-processed foods was associated with an increase of more than 10% greater risk of overall and breast cancer risk. The authors call for further studies to better understand the different elements of food processing and their association to cancer risk.
Abstract
OBJECTIVE To assess the prospective associations between consumption of ultra-processed food and risk of cancer. DESIGN Population based cohort study. SETTING AND PARTICIPANTS 104 980 participants aged at least 18 years (median age 42.8 years) from the French NutriNet-Santé cohort (2009-17). Dietary intakes were collected using repeated 24 hour dietary records, designed to register participants' usual consumption for 3300 different food items. These were categorised according to their degree of processing by the NOVA classification. MAIN OUTCOME MEASURES Associations between ultra-processed food intake and risk of overall, breast, prostate, and colorectal cancer assessed by multivariable Cox proportional hazard models adjusted for known risk factors. RESULTS Ultra-processed food intake was associated with higher overall cancer risk (n=2228 cases; hazard ratio for a 10% increment in the proportion of ultra-processed food in the diet 1.12 (95% confidence interval 1.06 to 1.18); P for trend<0.001) and breast cancer risk (n=739 cases; hazard ratio 1.11 (1.02 to 1.22); P for trend=0.02). These results remained statistically significant after adjustment for several markers of the nutritional quality of the diet (lipid, sodium, and carbohydrate intakes and/or a Western pattern derived by principal component analysis). CONCLUSIONS In this large prospective study, a 10% increase in the proportion of ultra-processed foods in the diet was associated with a significant increase of greater than 10% in risks of overall and breast cancer. Further studies are needed to better understand the relative effect of the various dimensions of processing (nutritional composition, food additives, contact materials, and neoformed contaminants) in these associations. STUDY REGISTRATION Clinicaltrials.gov NCT03335644.
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Dietary phytochemicals in breast cancer research: anticancer effects and potential utility for effective chemoprevention.
Kapinova, A, Kubatka, P, Golubnitschaja, O, Kello, M, Zubor, P, Solar, P, Pec, M
Environmental health and preventive medicine. 2018;23(1):36
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Bioactive phytochemicals are continually being studied for their role in cancer prevention with increasing evidence for flavonoids, carotenoids, phenolic acids, and organosulfur compounds (found in cruciferous vegetables). This 2018 review explores the protective effects of a broad spectrum of plant-derived substances. In total, more than 5000 individual phytochemicals have been identified in plant-derived foods, such as fruits, vegetables, and grains. These bioactive compounds have been shown to have antitumor activity, reduce inflammation, induce apoptosis (cell death), inhibit the proliferation of aggressive tumour cells, and impact on metastasis (migration of cancer cells). Specifically, in breast cancer, a few studies have examined phytochemicals on cancer stem cells (the originating tumour cells) and found that curcumin, genistein, indol-3-carbinol, c-phycocyanin, resveratrol, and quercetin downregulated their activity. Systematic reviews of dietary patterns and breast cancer show vegetables, and especially fibre, to be consistently protective against reduced risk of mammary carcinogenesis. Dietary polyphenols are considered a cost-effective approach to cancer care however there is still a lack of evidence due to the complex nature of combined phytochemicals versus isolated agents. Wholefood consumption is considered to improve bioavailability compared to supplementation however phytochemicals are a low-dose component of foods. There is also concern that some phytochemicals may act as carcinogens or tumour promoters (for example, beta-carotene). More clinical trials are required to fully understand phytochemicals and breast cancer care.
Abstract
Cancerous tissue transformation developing usually over years or even decades of life is a highly complex process involving strong stressors damaging DNA, chronic inflammation, comprehensive interaction between relevant molecular pathways, and cellular cross-talk within the neighboring tissues. Only the minor part of all cancer cases are caused by inborn predisposition; the absolute majority carry a sporadic character based on modifiable risk factors which play a central role in cancer prevention. Amongst most promising candidates for dietary supplements are bioactive phytochemicals demonstrating strong anticancer effects. Abundant evidence has been collected for beneficial effects of flavonoids, carotenoids, phenolic acids, and organosulfur compounds affecting a number of cancer-related pathways. Phytochemicals may positively affect processes of cell signaling, cell cycle regulation, oxidative stress response, and inflammation. They can modulate non-coding RNAs, upregulate tumor suppressive miRNAs, and downregulate oncogenic miRNAs that synergically inhibits cancer cell growth and cancer stem cell self-renewal. Potential clinical utility of the phytochemicals is discussed providing examples for chemoprevention against and therapy for human breast cancer. Expert recommendations are provided in the context of preventive medicine.
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Phytochemicals in Skin Cancer Prevention and Treatment: An Updated Review.
Ng, CY, Yen, H, Hsiao, HY, Su, SC
International journal of molecular sciences. 2018;19(4)
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This 2018 review discusses the anti-oxidative, anti-inflammatory, anti-proliferative, and anti-angiogenic effects of phytochemicals for the management of skin cancer. Melanoma and non-melanoma skin cancers are caused by cellular DNA damage, and as the skin is the body’s largest organ, it is most exposed to environmental stimulus. There are several promising phytochemicals in cancer chemoprevention including Epigallocatechin-3-gallate, resveratrol, curcumin, proanthocyanidins, silymarin, apigenin, capsaicin, genistein, indole-3-carbinol, and luteolin. Additionally, Gingerol has been applied topically to improve chemical stability in the skin. Caffeic Acid Phenethyl Ester (CAPE) is derived from bee propolis was shown to inhibit skin papilloma in animal studies. Capsaicin from red chillies induced apoptosis (cell death) in melanoma cells. Curcumin has been shown to modify numerous inflammatory markers including C-reactive protein and COX-2 whilst topically can promote remarkable symptomatic relief and reduce external cancer lesion size. Caffeic Acid exerts a protective effect towards skin cancer migration and invasion. EGCG has been shown to sensitize melanoma cells to inhibit growth, promote cell death and decrease cell proliferation. Genistein from soy has been shown to exert anti-angiogenesis properties, reduce tumour proliferation and metastasis. Resveratrol has a synergistic effect with other phytochemicals to suppress tumours. What all the studies reviewed show is the potential for phytochemicals in cancer treatment. They are widely available, cost effective and highly tolerated. They appear to have anti-carcinogenic effects through regulation of multiple different signalling pathways which help alter the typical progression of skin cancer.
Abstract
Skin is the largest human organ, our protection against various environmental assaults and noxious agents. Accumulation of these stress events may lead to the formation of skin cancers, including both melanoma and non-melanoma skin cancers. Although modern targeted therapies have ameliorated the management of cutaneous malignancies, a safer, more affordable, and more effective strategy for chemoprevention and treatment is clearly needed for the improvement of skin cancer care. Phytochemicals are biologically active compounds derived from plants and herbal products. These agents appear to be beneficial in the battle against cancer as they exert anti-carcinogenic effects and are widely available, highly tolerated, and cost-effective. Evidence has indicated that the anti-carcinogenic properties of phytochemicals are due to their anti-oxidative, anti-inflammatory, anti-proliferative, and anti-angiogenic effects. In this review, we discuss the preventive potential, therapeutic effects, bioavailability, and structure-activity relationship of these selected phytochemicals for the management of skin cancers. The knowledge compiled here will provide clues for future investigations on novel oncostatic phytochemicals and additional anti-skin cancer mechanisms.
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Weight Status and Alcohol Intake Modify the Association between Vitamin D and Breast Cancer Risk.
Deschasaux, M, Souberbielle, JC, Latino-Martel, P, Sutton, A, Charnaux, N, Druesne-Pecollo, N, Galan, P, Hercberg, S, Le Clerc, S, Kesse-Guyot, E, et al
The Journal of nutrition. 2016;146(3):576-85
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Experimental studies suggest that vitamin D may contribute to the prevention of breast cancer. However, population studies have been inconclusive, and it is possible that any relationship is dependent on other factors such as genetics or lifestyle. The objective of this study was to explore associations between blood vitamin D levels and breast cancer risk, along with 2 potential modifiers: body mass index (BMI; in kg/m(2)) and alcohol intake. The nested case-control study involved 233 women with breast cancer and 466 healthy controls. Overall, no association was found between vitamin D levels and breast cancer risk. However, a higher blood vitamin D concentration was associated with a decreased risk of breast cancer for women with a BMI under 22.4, whereas it was associated with an increased risk for women with a BMI 22.4 or over. A blood vitamin D concentration ≥ 10 ng/mL was associated with a decreased risk of breast cancer for women with alcohol intakes ≥ 7.1 g/day, whereas no association was observed for women with alcohol intakes < 7.1g/day. The authors concluded that BMI and alcohol intake modified the association between vitamin D and breast cancer risk. These lifestyle factors could explain the inconclusive results of previous studies.
Abstract
BACKGROUND Mechanistic hypotheses suggest that vitamin D may contribute to the prevention of breast cancer. However, epidemiologic evidence is inconsistent, suggesting a potential effect modification by individual factors. OBJECTIVE Our objective was to perform exploratory analyses on the prospective associations between the plasma 25-hydroxyvitamin D [25(OH)D] concentration, polymorphisms of genes encoding for the vitamin D receptor (VDR) and vitamin D-binding protein (also known as gc-globulin or group-specific component, GC), and breast cancer risk, along with 2 potential modifiers: body mass index (BMI; in kg/m(2)) and alcohol intake. METHODS A nested case-control study was set up in the SUpplémentation en VItamines et Minéraux Anti-oXydants (SU.VI.MAX) cohort (1994-2007), involving 233 women with breast cancer and 466 matched controls (mean ± SD age: 49 ± 6 y). The plasma total 25(OH)D concentration and gene polymorphisms were assessed on samples obtained at baseline. Conditional logistic regression models were computed. RESULTS A higher plasma 25(OH)D concentration was associated with a decreased risk of breast cancer for women with a BMI < the median of 22.4 [OR quartile (Q)4 compared with Q1: 0.46; 95% CI: 0.23, 0.89; P-trend = 0.01, P-interaction = 0.002], whereas it was associated with an increased risk for women with a BMI ≥ the median (OR Q4 compared with Q1: 2.45; 95% CI: 1.13, 5.28; P-trend = 0.02, P-interaction = 0.002). A plasma 25(OH)D concentration ≥ 10 ng/mL was associated with a decreased risk of breast cancer for women with alcohol intakes ≥ the median of 7.1 g/d (OR ≥10 compared with <10 ng/mL: 0.50; 95% CI: 0.26, 0.95; P = 0.03, P-interaction = 0.03). The genetic analyses were consistent with the results observed with plasma 25(OH)D. CONCLUSION In this prospective study, BMI and alcohol intake modified the association between vitamin D [plasma 25(OH)D and vitamin D-related gene polymorphisms] and breast cancer risk. These effect modifications suggest explanations for discrepancies in results of previous studies. This trial was registered at clinicaltrials.gov as NCT00272428.
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Associations between genes in the one-carbon metabolism pathway and advanced colorectal adenoma risk in individuals with low folate intake.
Han, SS, Sue, LY, Berndt, SI, Selhub, J, Burdette, LA, Rosenberg, PS, Ziegler, RG
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2012;21(3):417-27
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Colorectal cancer is the third most common cancer and third leading cause of cancer-related death in the US. Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. The aim of this study was to investigate associations between the risk of colorectal cancer and genes involved in one-carbon metabolism. Scientists looked at the folate intake, folate levels and genes of 500 people with advanced colorectal adenomas (benign tumours that have a high risk of becoming cancerous), and compared them to 500 healthy controls. Estimates of folate intake were based on a food frequency questionnaire which was completed by participants at the baseline of the study. Blood folate levels were also measured. People with the lowest intake of folate in their diets (0 to 262 micrograms/day) were at a 46% increased risk of advanced colorectal adenoma compared to people with the highest intakes (more than 466 micrograms/day). For those with the lowest intakes only, variations in several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) were associated with adenoma risk. There were no associations between gene variations and adenoma risk in people with higher intakes of folate. The authors concluded that folate intake may interact with variations in one-carbon metabolism genes to modify colorectal adenoma risk.
Abstract
BACKGROUND Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer. METHODS We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels. RESULTS Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 × 10(-5)]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 × 10(-5)). CONCLUSIONS AND IMPACT Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk.