Dataset Information

Blood Leukocyte AHRR Methylation and Risk of Non-smoking-associated Cancer: A Case-cohort Study of Non-Hodgkin Lymphoma.

ABSTRACT: Aryl-hydrocarbon receptor repressor (AHRR) hypomethylation in peripheral blood is tightly linked with tobacco smoking and lung cancer. Here, we investigated AHRR methylation in non-Hodgkin lymphoma (NHL), a non-smoking-associated cancer. In a case-cohort study within the population-based Danish Diet, Cancer and Health cohort, we measured AHRR (cg23576855) methylation in prediagnostic blood from 161 participants who developed NHL within 13.4 years of follow-up (median: 8.5 years), with a comparison group of 164 randomly chosen participants. We measured DNA-methylation levels using bisulfite pyrosequencing and estimated incidence rate ratios (IRR) using Cox proportional hazards models with adjustment for baseline age, sex, educational level, smoking status, body mass index, alcohol intake, physical activity, and diet score. Global DNA-methylation levels were assessed by long interspersed nucleotide element 1 (LINE-1) analysis. Overall, the IRR for AHRR hypomethylation (lowest vs. other quartiles) was 2.52 [95% confidence interval (CI), 1.24-5.15]. When stratified according to time between blood draw and diagnosis, low AHRR methylation levels were associated with a future diagnosis of NHL [IRR: 4.50 (95% CI, 1.62-12.50) at 0-<5 years, 7.04 (95% CI, 2.36-21.02) at 5-<10 years, and 0.56 (95% CI, 0.21-1.45) at ≥10 years]. There was no association between global DNA-methylation levels and risk of NHL. Our results show that AHRR hypomethylation in blood leukocytes is associated with a higher risk of NHL in a time-dependent manner, suggesting that it occurs as a response to tumor development.

Significance

Our population-based study demonstrated that lower AHRR methylation levels in peripheral blood leukocytes were associated with an increased risk of NHL. This association was independent of tobacco smoking, sex, and lifestyle characteristics, but was highly dependent on time to diagnosis. These findings highlight the potential of AHRR methylation as a biomarker for NHL risk, effective up to 10 years after blood draw.

SUBMITTER: Dahl C

PROVIDER: S-EPMC10484117 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Blood Leukocyte AHRR Methylation and Risk of Non-smoking-associated Cancer: A Case-cohort Study of Non-Hodgkin Lymphoma.

Dahl Christina C Hvidtfeldt Ulla A UA Tjønneland Anne A Guldberg Per P Raaschou-Nielsen Ole O

Cancer research communications 20230907 9

Aryl-hydrocarbon receptor repressor (AHRR) hypomethylation in peripheral blood is tightly linked with tobacco smoking and lung cancer. Here, we investigated AHRR methylation in non-Hodgkin lymphoma (NHL), a non-smoking-associated cancer. In a case-cohort study within the population-based Danish Diet, Cancer and Health cohort, we measured AHRR (cg23576855) methylation in prediagnostic blood from 161 participants who developed NHL within 13.4 years of follow-up (median: 8.5 ye ...[more]

PMID: 37691855

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Project description:BackgroundNon-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.MethodsWe pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).ResultsRisks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.ConclusionsUsing a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

Project description:BackgroundDNA methylation is associated with cancer, metabolic, neurological, and autoimmune disorders. Hypomethylation of aryl hydrocarbon receptor repressor (AHRR) especially at cg05575921 is associated with smoking and lung cancer. Studies on the association between AHRR methylation at cg05575921 and sources of polycyclic aromatic hydrocarbon (PAH) other than smoking are limited. The aim of our study was to assess the pattern of blood DNA methylation at cg05575921 in non-smoking Taiwanese adults living in areas with different PM2.5 levels.MethodsData on blood DNA methylation, smoking, and residence were retrieved from the Taiwan Biobank dataset (2008-2015). Current and former smokers, as well as individuals with incomplete information were excluded from the current study. The final analysis included 708 participants (279 men and 429 women) aged 30-70 years. PM2.5 levels have been shown to increase as one moves from the northern through central towards southern Taiwan. Based on this trend, the study areas were categorized into northern, north-central, central, and southern regions.ResultsLiving in PM2.5 areas was associated with lower methylation levels: compared with the northern area (reference area), living in north-central, central, and southern areas was associated with lower methylation levels at cg05575921. However, only methylation levels in those living in central and southern areas were significant (β = - 0.01003, P = 0.009 and β = - 0.01480, P < 0.001, respectively. Even though methylation levels in those living in the north-central area were not statistically significant, the test for linear trend was significant (P < 0.001). When PM2.5 was included in the regression model, a unit increase in PM2.5 was associated with 0.00115 (P < 0.001) lower cg05575921 methylation levels.ConclusionLiving in PM2.5 areas was inversely associated with blood AHRR methylation levels at cg05575921. The methylation levels were lowest in participants residing in southern followed by central and north-central areas. Moreover, when PM2.5 was included in the regression model, it was inversely associated with methylation levels at cg05575921. Blood methylation at cg05575921 (AHRR) in non-smokers might indicate different exposures to PM2.5 and lung cancer which is a PM2.5-related disease.

Project description:BackgroundNumerous studies have demonstrated that DNA methylation levels in the aryl hydrocarbon receptor repressor (AHRR) gene measured in cord blood are significantly associated with prenatal tobacco smoke exposure and can be used as a fetal exposure biomarker. The mechanism driving this demethylation has not been determined and it is unclear if all cord blood cell types are impacted. Nucleated red blood cells (nRBCs/CD235a+ cells) are developmentally immature RBCs that display genome-wide hypomethylation and are observed at increased frequency in the cord blood of smoking mothers. We tested if AHRR methylation levels in CD235a+ nRBCs or nRBC counts influenced AHRR methylation in whole cord blood.MethodsCord blood was collected from smoking (n = 34) and nonsmoking (n = 19) mothers and DNA was prepared from whole cord blood, isolated CD235a+ nRBCs, and CD14+ monocytes. AHRR methylation in cord blood DNA was measured using Illumina 850K arrays (cg05575921, chr5:373378). Pyrosequencing was used to compare methylation levels among cord blood, CD235a+, and CD14+ cells. We measured nRBC percentages using conventional complete blood counts and estimated percent nRBCs by a deconvolution model.ResultsMethylation levels in AHRR were significantly lower in nRBCs relative to whole cord blood and CD14+ monocytes. While AHRR methylation levels in the cell types were significantly correlated across all subjects, methylation values at the chr5:373378 CpG averaged 14.6% lower in nRBCs (range 0.4 to 24.8%; p = 3.8E-13) relative to CD14+, with nonsmokers showing a significantly greater hypomethylation (- 4.1%, p = 1.8E-02). Methylation level at the AHRR chr5:373378 CpG was strongly associated with self-reported smoking in both CD14+ monocytes (t test p = 5.7E-09) and nRBCs (p = 4.8E-08), as well as cotinine levels (regression p = 1.1E-07 and p = 3.6E-04, respectively). For subjects with whole blood 850K data, robust linear regression models adjusting for estimated cell type composition, either including nRBCs counts or estimates, modestly increased the association between smoking and cg05575921 methylation.ConclusionsPrenatal smoke exposure was highly significantly associated with AHRR methylation in cord blood, CD14+ monocytes, and CD235a+ nRBCs. AHRR methylation levels in nRBCs and nRBC counts had minimal effect on cord blood methylation measurements. However, regression models using estimated nRBCs or actual nRBC counts outperformed those lacking these covariates.

Dataset Information

Blood Leukocyte AHRR Methylation and Risk of Non-smoking-associated Cancer: A Case-cohort Study of Non-Hodgkin Lymphoma.

Significance

Publications

Blood Leukocyte <i>AHRR</i> Methylation and Risk of Non-smoking-associated Cancer: A Case-cohort Study of Non-Hodgkin Lymphoma.

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