BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.

• MeSH
• adenokarcinom metabolismus   MeSH
• genotyp MeSH
• hepcidiny genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory slinivky břišní metabolismus   MeSH
• regulace genové exprese u nádorů fyziologie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• vazebná nerovnováha MeSH
• železo metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

• MeSH
• adipozita genetika   MeSH
• celogenomová asociační studie statistika a číselné údaje   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• index tělesné hmotnosti MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory epidemiologie   etiologie   genetika   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mendelovská randomizace MeSH
• metabolom genetika   MeSH
• obezita komplikace   epidemiologie   genetika   metabolismus   MeSH
• poměr pasu a boků MeSH
• rizikové faktory MeSH
• sexuální faktory MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival. METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed between June 1, 1983, and Dec 31, 2019. Eligible patients had smoking data before NSCLC diagnosis, epidemiological data at diagnosis (obtained largely from patient questionnaires), and clinical information (retrieved from medical records). Kaplan-Meier curves and multivariable Cox models (ie, adjusted hazard ratios [aHRs]) were generated with individual, harmonised patient data from the consortium database. We estimated overall survival for all causes, measured in years from diagnosis date until the date of the last follow-up or death due to any cause and NSCLC-specific survival. FINDINGS: Of 42 087 patients with NSCLC in the COS-ILCCO database, 21 893 (52·0%) of whom were male and 20 194 (48·0%) of whom were female, we excluded 4474 (10·6%) with missing data. Compared with current smokers (15 036 [40·0%] of 37 613), patients with 1-3 years of smoking abstinence before NSCLC diagnosis (2890 [7·7%]) had an overall survival aHR of 0·92 (95% CI 0·87-0·97), patients with 3-5 years of smoking abstinence (1114 [3·0%]) had an overall survival aHR of 0·90 (0·83-0·97), and patients with more than 5 years of smoking abstinence (10 841 [28·8%]) had an overall survival aHR of 0·90 (0·87-0·93). Improved NSCLC-specific survival was observed in 4301 (44%) of 9727 patients who had quit cigarette smoking and was significant at abstinence durations of more than 5 years (aHR 0·87, 95% CI 0·81-0·93). Results were consistent across age, sex, histology, and disease-stage distributions. INTERPRETATION: In this large, pooled analysis of cohort studies across Asia, Europe, North America, and South America, overall survival was improved in patients with NSCLC whose duration of smoking abstinence before diagnosis was as short as 1 year. These findings suggest that quitting smoking can improve overall survival, even if NSCLC is diagnosed at a later lung-cancer screening visit. These findings also support the implementation of public health smoking cessation strategies at any time. FUNDING: The Alan B Brown Chair, The Posluns Family Fund, The Lusi Wong Fund, and the Princess Margaret Cancer Foundation.

• MeSH
• kohortové studie MeSH
• kouření epidemiologie   MeSH
• lidé MeSH
• nádory plic * diagnóza   MeSH
• nemalobuněčný karcinom plic * diagnóza   MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Diabetes is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship still require investigation and it is not known if the association is modified by genetic variants. To address these questions, we undertook a genome-wide gene-environment interaction analysis. METHODS: We used data from 3 genetic consortia (CCFR, CORECT, GECCO; 31,318 colorectal cancer cases/41,499 controls) and undertook genome-wide gene-environment interaction analyses with colorectal cancer risk, including interaction tests of genetics(G)xdiabetes (1-degree of freedom; d.f.) and joint testing of Gxdiabetes, G-colorectal cancer association (2-d.f. joint test) and G-diabetes correlation (3-d.f. joint test). RESULTS: Based on the joint tests, we found that the association of diabetes with colorectal cancer risk is modified by loci on chromosomes 8q24.11 (rs3802177, SLC30A8 - ORAA: 1.62, 95% CI: 1.34-1.96; ORAG: 1.41, 95% CI: 1.30-1.54; ORGG: 1.22, 95% CI: 1.13-1.31; p-value3-d.f.: 5.46 × 10-11) and 13q14.13 (rs9526201, LRCH1 - ORGG: 2.11, 95% CI: 1.56-2.83; ORGA: 1.52, 95% CI: 1.38-1.68; ORAA: 1.13, 95% CI: 1.06-1.21; p-value2-d.f.: 7.84 × 10-09). DISCUSSION: These results suggest that variation in genes related to insulin signaling (SLC30A8) and immune function (LRCH1) may modify the association of diabetes with colorectal cancer risk and provide novel insights into the biology underlying the diabetes and colorectal cancer relationship.

• MeSH
• celogenomová asociační studie metody   MeSH
• diabetes mellitus * genetika   MeSH
• genetická predispozice k nemoci MeSH
• interakce genů a prostředí MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * genetika   MeSH
• lidé MeSH
• mikrofilamentové proteiny genetika   MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH