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Background: A growing body of evidence suggests that alterations of dietary fatty acid (FA) profiles are associated with colorectal cancer risk. However, data from large-scale epidemiologic studies using circulating FA measurements to objectively assess individual FA and FA categories are scarce., Methods: We investigate the association between red blood cell (RBC) membrane FAs and risk of colorectal cancer in a case-control study nested within a large prospective cohort. After a median follow-up of 6.4 years, 1,069 incident colorectal cancer cases were identified and matched to 1,069 controls among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). The FA composition of RBC phospholipids (in mol%) was analyzed by gas chromatography, and their association with risk of colorectal cancer was estimated by multivariable adjusted conditional logistic regression models., Results: After correction for multiple testing, subjects with higher concentrations of RBC stearic acid were at higher risk for colorectal cancer (OR = 1.23; 95% CI = 1.07-1.42, per 1 mol%). Conversely, colorectal cancer incidence decreased with increasing proportions of RBC n-3 PUFA, particularly eicosapentaenoic acid (0.75; 0.62-0.92, per 1 mol%). The findings for the n-6 PUFA arachidonic acid were inconsistent., Conclusions: The positive association between prediagnostic RBC stearic acid and colorectal cancer reflects putative differences in FA intake and metabolism between cancer cases and matched controls, which deserve further investigation. The inverse relationship between EPA and colorectal cancer is in line with the repeatedly reported protective effect of fish consumption on colorectal cancer risk., Impact: These findings add to the evidence on colorectal cancer prevention., (©2021 American Association for Cancer Research.)

Background: Fatty acids impact obesity, estrogens, and inflammation, which are risk factors for ovarian cancer. Few epidemiologic studies have investigated the association of fatty acids with ovarian cancer., Methods: Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 1,486 incident ovarian cancer cases were identified. Cox proportional hazard models with adjustment for ovarian cancer risk factors were used to estimate HRs of ovarian cancer across quintiles of intake of fatty acids. False discovery rate was computed to control for multiple testing. Multivariable conditional logistic regression models were used to estimate ORs of ovarian cancer across tertiles of plasma fatty acids among 633 cases and two matched controls in a nested case-control analysis., Results: A positive association was found between ovarian cancer and intake of industrial trans elaidic acid [HR comparing fifth with first quintile Q5-Q1 = 1.29; 95% confidence interval (CI) = 1.03-1.62; P trend = 0.02, q-value = 0.06]. Dietary intakes of n -6 linoleic acid (HR Q5-Q1 = 1.10; 95% CI = 1.01-1.21; P trend = 0.03) and n -3 α-linolenic acid (HR Q5-Q1 = 1.18; 95% CI = 1.05-1.34; P trend = 0.007) from deep-frying fats were also positively associated with ovarian cancer. Suggestive associations were reported for circulating elaidic (OR comparing third with first tertile T3-T1 = 1.39; 95% CI = 0.99-1.94; P trend = 0.06) and α-linolenic acids (OR T3-T1 = 1.30; 95% CI = 0.98-1.72; P trend = 0.06)., Conclusions: Our results suggest that higher intakes and circulating levels of industrial trans elaidic acid, and higher intakes of linoleic acid and α-linolenic acid from deep-frying fat, may be associated with greater risk of ovarian cancer., Impact: If causal, eliminating industrial trans -fatty acids could offer a straightforward public health action for reducing ovarian cancer risk., (©2020 American Association for Cancer Research.)

Background: The "meeting-in-the-middle" (MITM) is a principle to identify exposure biomarkers that are also predictors of disease. The MITM statistical framework was applied in a nested case-control study of hepatocellular carcinoma (HCC) within European Prospective Investigation into Cancer and Nutrition (EPIC), where healthy lifestyle index (HLI) variables were related to targeted serum metabolites. Methods: Lifestyle and targeted metabolomic data were available from 147 incident HCC cases and 147 matched controls. Partial least squares analysis related 7 lifestyle variables from a modified HLI to a set of 132 serum-measured metabolites and a liver function score. Mediation analysis evaluated whether metabolic profiles mediated the relationship between each lifestyle exposure and HCC risk. Results: Exposure-related metabolic signatures were identified. Particularly, the body mass index (BMI)-associated metabolic component was positively related to glutamic acid, tyrosine, PC aaC38:3, and liver function score and negatively to lysoPC aC17:0 and aC18:2. The lifetime alcohol-specific signature had negative loadings on sphingomyelins (SM C16:1, C18:1, SM(OH) C14:1, C16:1 and C22:2). Both exposures were associated with increased HCC with total effects (TE) = 1.23 (95% confidence interval = 0.93-1.62) and 1.40 (1.14-1.72), respectively, for BMI and alcohol consumption. Both metabolic signatures mediated the association between BMI and lifetime alcohol consumption and HCC with natural indirect effects, respectively, equal to 1.56 (1.24-1.96) and 1.09 (1.03-1.15), accounting for a proportion mediated of 100% and 24%. Conclusions: In a refined MITM framework, relevant metabolic signatures were identified as mediators in the relationship between lifestyle exposures and HCC risk. Impact: The understanding of the biological basis for the relationship between modifiable exposures and cancer would pave avenues for clinical and public health interventions on metabolic mediators. Cancer Epidemiol Biomarkers Prev; 27(5); 531-40. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Although dietary fatty acids may influence colorectal carcinogenesis, few studies have examined the association with adenoma risk. We assessed the association between biomarkers of dietary fatty acids or metabolism of fatty acids and the risk of colorectal adenomas in a nested case-control study from the French E3N-EPIC cohort., Methods: Among 13,106 women without prevalent cancer who completed the diet history questionnaire and who provided blood samples, 328 cases of adenomatous polyp were identified during an average of 6.6-year follow-up and randomly matched to 619 polyp-free colonoscopy controls. Erythrocyte membrane phospholipid fatty acid concentrations were determined by gas chromatography. Adjusted ORs for risk of colorectal adenomas with increasing concentrations of fatty acids were calculated using conditional logistic regression, separately for advanced and nonadvanced adenomas., Results: Associations were stronger with advanced than nonadvanced adenomas. High concentration of pentadecanoate plus heptadecanoate acids were inversely associated with the risk of advanced adenomas [highest vs. lowest tertile: OR(T3vsT1) = 0.40 (95% confidence interval (CI) 0.20-0.79); P(trend) = 0.009]. Oleic acid was associated with an increased risk of advanced adenomas [OR(T3vsT1) = 2.32 (1.16-4.64); P(trend) = 0.018]. Some polyunsaturated fatty acids were associated with the risk of advanced adenomas, either positively for di-homo-γ-linolenate [OR(T3vsT1) = 2.07 (1.15-3.72); P(trend) = 0.013], or negatively for eicosapentaenoic and docosahexaenoic acids [OR(T3vsT1) = 0.50 (0.27-0.93); P(trend) = 0.044 and OR(T3vsT1) = 0.50 (0.26-0.96); P(trend) = 0.028, respectively]., Conclusion: A specific erythrocyte membrane phospholipid fatty acid profile, presumably reflecting both a complex dietary pattern and altered fatty acid metabolism, is associated with advanced colorectal adenoma risk., Impact: Adenomas could be a target for primary prevention of colorectal cancer, using interventional strategy based on lipidomic profile of patients., (©2013 AACR)

Background: ω-3 polyunsaturated fatty acids (PUFA) could play a protective role on the risk of breast cancer; however, little is known about this relation among Mexican women. We evaluated the association between ω-3 and ω-6 PUFA intake and breast cancer risk by obesity status in Mexican women., Methods: A population-based case-control study was conducted in Mexico, including 1,000 incident breast cancer cases and 1,074 controls matched to cases by age, health care system, and region. Women provided information on health and diet by in-person interview. Body mass index (BMI) measures were used to define overall obesity. Obesity status was categorized as normal weight (18.5 < BMI < 25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30). A conditional logistic regression model was used to assess the association between PUFA and breast cancer risk., Results: Overall, there was no significant association between ω-3 PUFA intake and breast cancer risk (P = 0.31). An increased risk of breast cancer was associated with increasing ω-6 PUFA intake in premenopausal women [OR = 1.92, 95% confidence interval (CI) = 1.13-3.26; P = 0.04]. A decreased risk of breast cancer was significantly associated with increasing ω-3 PUFA intake in obese women (OR = 0.58, 95% CI = 0.39-0.87; P = 0.008) but not in normal weight nor in overweight women (P(heterogeneity) = 0.017)., Conclusions: Obesity status may affect the association between ω-3 PUFA intake and breast cancer risk. The underlying mechanisms may be related to decreased inflammation and improved adipokin and estrogen levels induced by ω-3 PUFA in adipose tissue in obese women., Impact: Increased intake of ω-3 PUFA should be recommended among Mexican women in particular in obese women., (©2011 AACR.)

A key fatty acid synthesis enzyme, acetyl-CoA carboxylase alpha (ACC-alpha), has been shown to be highly expressed in human breast cancer and other tumor types and also to specifically interact with the protein coded by one of two major breast cancer susceptibility genes BRCA1. We used a comprehensive haplotype analysis to examine the contribution of the ACC-alpha common genetic variation (allele frequency >5%) to breast cancer in a case-control study (1,588 cases/2,600 controls) nested within the European Prospective Investigation into Cancer and Nutrition. We identified 21 haplotype-tagging polymorphisms efficiently capturing common variation within 325 kb of ACC-alpha and surrounding sequences using genotype data from the HapMap project and our resequencing data. We found an effect on overall risk of breast cancer in homozygous carriers of one common haplotype [odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.03-2.94]. When the data were subdivided by menopausal status, we found statistical evidence of heterogeneity for two other common haplotypes (P value for heterogeneity = 0.016 and 0.045). In premenopausal women, the carriers of these haplotypes, compared with noncarriers, had an altered risk of breast cancer (OR, 0.70; 95% CI, 0.53-0.92 and OR, 1.35; 95% CI, 1.04-1.76). These findings were not significant after adjustment for multiple testing and therefore should be considered as preliminary and evaluated in larger independent studies. However, they suggest a possible role of the ACC-alpha common sequence variants in susceptibility to breast cancer and encourage studies of other genes involved in fatty acid synthesis.

Activation of de novo fatty acid synthesis is a characteristic feature of cancer cells. We have recently described an interaction between acetyl-CoA carboxylase alpha (ACCalpha), a key enzyme in fatty acid synthesis, and BRCA1, which indicates a possible connection between lipid synthesis and genetic factors involved in susceptibility to breast and ovarian cancers. For this reason, we explored the role of ACCalpha in breast cancer cell survival using an RNA interference (RNAi) approach. We show that specific silencing of either the ACCalpha or the fatty acid synthase (FAS) genes in cancer cells results in a major decrease in palmitic acid synthesis. Depletion of the cellular pool of palmitic acid is associated with induction of apoptosis concomitant with the formation of reactive oxygen species (ROS) and mitochondrial impairment. Expression of a small interfering RNA (siRNA)-resistant form of ACCalpha mRNA prevented the effect of ACCalpha-RNAi but failed to prevent the effect of FAS gene silencing. Furthermore, supplementation of the culture medium with palmitate or with the antioxidant vitamin E resulted in the complete rescue of cells from both ACCalpha and FAS siRNA-induced apoptosis. Finally, human mammary epithelial cells are resistant to RNAi against either ACCalpha or FAS. These data confirm the importance of lipogenesis in cancer cell survival and indicate that this pathway represents a key target for antineoplastic therapy that, however, might require specific dietary recommendation for full efficacy.

Insulin-like growth factor-I (IGF-I) stimulates cell proliferation and can enhance the development of tumors in different organs. Epidemiologic studies have shown that an elevated level of circulating IGF-I is associated to increased risk of breast cancer as well as other cancers. Genetic variants affecting the release or biological action of growth hormone (GH), the main stimulator of IGF-I production, may predict circulating levels of IGF-I and have an effect on cancer risk. We tested this hypothesis with a large case-control study of 807 breast cancer patients and 1,588 matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We genotyped 22 common single nucleotide polymorphisms in 10 genes involved in GH production and action (GHRH, GHRHR, SST, SSTR1-SSTR5, POU1F1, and GH1), and in parallel, we measured serum levels of IGF-I and IGFBP-3, its major binding protein, in samples of cases and controls. SST and SSTR2 polymorphisms showed weak but statistically significant associations with breast cancer risk. SSTR5 polymorphisms were associated with IGF-I levels, whereas one polymorphism in GHRHR and one in POU1F1 were associated with IGFBP-3 levels. Our conclusion is that common genetic variation in the GH synthesis pathway, as measured by single nucleotide polymorphisms selected in the present study, is not a major determinant of IGF-I and IGFBP-3 circulating levels, and it does not play a major role in altering breast cancer risk.