The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Medical history, lifestyle, family history, and occupational risk factors for mantle cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: The etiology of mantle cell lymphoma (MCL), a distinctive subtype accounting for 2%-10% of all non-Hodgkin lymphoma, is not known. METHODS: We investigated associations with self-reported medical history, lifestyle, family history, and occupational risk factors in a pooled analysis of 557 patients with MCL and 13766 controls from 13 case-control studies in Europe, North America, and Australia. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each exposure were examined using multivariate logistic regression models. RESULTS: The median age of the MCL patients was 62 years and 76% were men. Risk of MCL was inversely associated with history of hay fever (OR = 0.63, 95% CI = 0.48 to 0.82), and the association was independent of other atopic diseases and allergies. A hematological malignancy among first-degree relatives was associated with a twofold increased risk of MCL (OR = 1.99, 95% CI = 1.39 to 2.84), which was stronger in men (OR = 2.21, 95% CI = 1.44 to 3.38) than women (OR = 1.61, 95% CI = 0.82 to 3.19). A modestly increased risk of MCL was also observed in association with ever having lived on a farm (OR = 1.40, 95% CI = 1.03 to 1.90). Unlike some other non-Hodgkin lymphoma subtypes, MCL risk was not statistically significantly associated with autoimmune disorders, tobacco smoking, alcohol intake, body mass index, or ultraviolet radiation. CONCLUSIONS: The novel observations of a possible role for atopy and allergy and farm life in risk of MCL, together with confirmatory evidence of a familial link, suggest a multifactorial etiology of immune-related environmental exposures and genetic susceptibility. These findings provide guidance for future research in MCL etiology.

Trans fatty acid intake is associated with increased risk and n3 fatty acid intake with reduced risk of non-hodgkin lymphoma.

We evaluated the association of dietary fat and protein intake with risk of non-Hodgkin lymphoma (NHL) in a clinic-based study in 603 cases (including 218 chronic lymphocytic leukemia/small lymphocytic lymphoma, 146 follicular lymphoma, and 105 diffuse large B-cell lymphoma) and 1007 frequency-matched controls. Usual diet was assessed with a 128-item food-frequency questionnaire. Unconditional logistic regression was used to estimate ORs and 95% CIs, and polytomous logistic regression was used to assess subtype-specific risks. trans Fatty acid (TFA) intake was positively associated with NHL risk [OR = 1.60 for highest vs. lowest quartile (95% CI = 1.18, 2.15); P-trend = 0.0014], n3 (ω3) fatty acid intake was inversely associated with risk [OR = 0.48 (95% CI = 0.35, 0.65); P-trend < 0.0001], and there was no association with total, animal, plant-based, or saturated fat intake. When examining intake of specific foods, processed meat [OR = 1.37 (95% CI = 1.02, 1.83); P-trend = 0.03], milk containing any fat [OR = 1.47 (95% CI = 1.16, 1.88); P-trend = 0.0025], and high-fat ice cream [OR = 4.03 (95% CI = 2.80, 5.80); P-trend < 0.0001], intakes were positively associated with risk, whereas intakes of fresh fish and total seafood [OR = 0.61 (95% CI = 0.46, 0.80); P-trend = 0.0025] were inversely associated with risk. Overall, there was little evidence for NHL subtype-specific heterogeneity. In conclusion, diets high in TFAs, processed meats, and higher fat dairy products were positively associated with NHL risk, whereas diets high in n3 fatty acids and total seafood were inversely associated with risk.

Food-frequency questionnaire-based estimates of total antioxidant capacity and risk of non-Hodgkin lymphoma.

Antioxidants, primarily from fruits and vegetables, have been hypothesized to protect against non-Hodgkin lymphoma (NHL). The oxygen radical absorbance capacity (ORAC) assay, which measures total antioxidant capacity of individual foods and accounts for synergism, can be estimated using a food-frequency questionnaire (FFQ). We tested the hypothesis that higher intake of antioxidant nutrients from foods, supplements and FFQ-based ORAC values are associated with a lower risk of NHL in a clinic-based study of 603 incident cases and 1,007 frequency-matched controls. Diet was assessed with a 128-item FFQ. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals adjusted for age, sex, residence and total energy. Dietary intake of α-tocopherol (OR=0.50; p-trend=0.0002), ß-carotene (OR=0.58; p-trend=0.0005), lutein/zeaxanthin (OR=0.62; p-trend=0.005), zinc (OR=0.54; p-trend=0.003) and chromium (OR=0.68; p-trend=0.032) was inversely associated with NHL risk. Inclusion of supplement use had little impact on these associations. Total vegetables (OR=0.52; p-trend<0.0001), particularly green leafy (OR=0.52; p-trend<0.0001) and cruciferous (OR=0.68; p-trend=0.045) vegetables, were inversely associated with NHL risk. NHL risk was inversely associated with both hydrophilic ORAC (OR=0.61, p-trend=0.003) and lipophilic ORAC (OR=0.48, p-trend=0.0002), although after simultaneous adjustment for other antioxidants or total vegetables, only the association for lipophilic ORAC remained significant. There was no striking heterogeneity in results across the common NHL subtypes. Higher antioxidant intake as estimated by the FFQ-ORAC, particularly the lipophilic component, was associated with a lower NHL risk after accounting for other antioxidant nutrients and vegetable intake, supporting this as potentially useful summary measure of total antioxidant intake.