Long-term exposure to air pollution has been associated with several adverse health effects including cardiovascular, respiratory diseases and cancers. However, underlying molecular alterations ...remain to be further investigated. The aim of this study is to investigate the effects of long-term exposure to air pollutants on (a) average DNA methylation at functional regions and, (b) individual differentially methylated CpG sites. An assumption is that omic measurements, including the methylome, are more sensitive to low doses than hard health outcomes.
This study included blood-derived DNA methylation (Illumina-HM450 methylation) for 454 Italian and 159 Dutch participants from the European Prospective Investigation into Cancer and Nutrition (EPIC). Long-term air pollution exposure levels, including NO2, NOx, PM2.5, PMcoarse, PM10, PM2.5 absorbance (soot) were estimated using models developed within the ESCAPE project, and back-extrapolated to the time of sampling when possible. We meta-analysed the associations between the air pollutants and global DNA methylation, methylation in functional regions and epigenome-wide methylation. CpG sites found differentially methylated with air pollution were further investigated for functional interpretation in an independent population (EnviroGenoMarkers project), where (N=613) participants had both methylation and gene expression data available.
Exposure to NO2 was associated with a significant global somatic hypomethylation (p-value=0.014). Hypomethylation of CpG island's shores and shelves and gene bodies was significantly associated with higher exposures to NO2 and NOx. Meta-analysing the epigenome-wide findings of the 2 cohorts did not show genome-wide significant associations at single CpG site level. However, several significant CpG were found if the analyses were separated by countries. By regressing gene expression levels against methylation levels of the exposure-related CpG sites, we identified several significant CpG-transcript pairs and highlighted 5 enriched pathways for NO2 and 9 for NOx mainly related to the immune system and its regulation.
Our findings support results on global hypomethylation associated with air pollution, and suggest that the shores and shelves of CpG islands and gene bodies are mostly affected by higher exposure to NO2 and NOx. Functional differences in the immune system were suggested by transcriptome analyses.
•We studied the effects of long-term exposure to air pollutants on DNA methylation.•A consistent global hypomethylation was observed for exposure to ambient NO2 and NOx.•This hypomethylation was observed for CpG island's shores, shelves and gene bodies.•No CpG sites were epigenome-wide significant in a combined analysis of a low and high exposed cohort.
Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the ...association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow‐up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country‐specific dietary questionnaires and the Phenol‐Explorer database. In multivariable‐adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HRQ4 vs. Q1 = 0.99, 95% confidence interval CI 0.77–1.29), papillary (HRQ4 vs. Q1 = 1.06, 95% CI 0.80–1.41) or follicular TC (HRQ4 vs. Q1 = 1.10, 95% CI 0.55–2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p‐trend = 0.019) and phenolic acids (p‐trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals.
What's new?
Polyphenols are secondary plant metabolites with health protective properties but whether a diet rich in polyphenols protects from thyroid cancer has not been conclusively explored. In this large prospective study, no associations were observed between dietary polyphenol intake and differentiated thyroid cancer risk. The authors recommend further studies to investigate potential associations specifically in overweight and obese individuals.
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the ...primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (OR
= 2.30, 95% confidence intervals CI: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time–risk relationship are unclear, and there is limited information on ...the role of antidiabetic medications.
We analyzed individual-level data from 15 case–control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates.
Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72–2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03–1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14–0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75–8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53–1.70, for ≥15 years).
This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration–risk relationship.
Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ...(“ApoA2‐ATQ/AT”), alone and in combination with carbohydrate antigen 19–9 (CA19‐9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19‐9 and ApoA2‐ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag‐time. For CA19‐9, in univariate marker analyses, C‐statistics to distinguish future pancreatic cancer patients from cancer‐free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6–18 months; for ApoA2‐ATQ/AT, C‐statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2‐ATQ/AT plus CA19‐9 significantly improved discrimination within >6–18 months (C = 0.74 vs. 0.71 for CA19‐9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6–18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19‐9 combined with ApoA2‐ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19‐9 alone. Compared to CA19‐9 alone, the combination of CA19‐9 and ApoA2‐ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.
What's new?
A new biomarker may boost sensitivity of early pancreatic cancer testing. Because the disease is rare, and most cases arise sporadically, screening focused on patients with a family history is inadequate, but general‐population screening remains impractical. Here, the authors investigated a newly identified biomarker for pancreatic cancer, an isoform of apolipoprotein A2 called ApoA2‐ATQ/AT. They tested pre‐diagnosis blood samples collected from the EPIC cohort and looked at ApoA2‐ATQ/AT in combination with the commonly used biomarker, CA19‐9. Using both markers together enabled earlier detection of cancer than CA19‐9 alone, up to 18 months before diagnosis.
Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) ...consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676‐rs409627, TERT‐rs2736100, CTC1‐rs3027234, DHX35‐rs6028466, PXK‐rs6772228, NAF1‐rs7675998, ZNF208‐rs8105767, OBFC1‐rs9420907, ACYP2‐rs11125529 and TERC‐rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT‐rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1‐rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome‐wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome‐wide candidate SNP for PDAC risk (TERT‐rs2736100), a completely new signal (NAF1‐rs7675998) approaching genome‐wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.
What's new?
How does lymphocyte telomere length affect pancreatic cancer risk? These authors analyzed 10 SNPs associated with telomere length and their relationship with pancreatic cancer risk, using data from the Pancreatic Disease Research (PANDoRA) consortium. Each patient received a “teloscore” based on the combined SNP data, and it turned out that a low teloscore ‐ predicting a short telomere ‐ was associated with increased pancreatic cancer risk. The researchers also identified for the first time a significant genome‐wide association between a SNP, TERT‐rs2736100, and increased pancreatic cancer risk. They also discovered a completely novel association between a SNP, NAF1‐rs7675998, and decreased risk.
Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack‐years and a dose‐response relationship with increasing pack‐years of smoking ...between menarche and first full‐term pregnancy (FFTP). Studies with comprehensive quantitative life‐time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) 95% confidence interval (CI) 1.16 1.05–1.28, 1.14 1.04–1.25 and 1.10 1.01–1.20, respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack‐years from menarche to FFTP (1.73 1.29–2.32 for every increase of 20 pack‐years) while pack‐years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34–0.82 for every increase of 20 pack‐years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious.
What's new?
The EPIC study is the largest cohort analysis on smoking and breast cancer to date. In this analysis of data from that study, the authors have confirmed that both active and passive exposure to cigarette smoke increases breast cancer risk. These results emphasize that it's important to distinguish between passive exposure and no exposure when analyzing the relationship between smoking and breast cancer. The authors also confirm that the most potent window of exposure for smoking and breast cancer risk is between menarche and first full term pregnancy.
It has been estimated that at least a third of the most common cancers are related to lifestyle and as such are preventable. Key modifiable lifestyle factors have been individually associated with ...cancer risk; however, less is known about the combined effects of these factors. This study generated a healthy lifestyle index score (HLIS) to investigate the joint effect of modifiable factors on the risk of overall cancers, alcohol-related cancers, tobacco-related cancers, obesity-related cancers, and reproductive-related cancers. The study included 391,608 men and women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The HLIS was constructed from 5 factors assessed at baseline (diet, physical activity, smoking, alcohol consumption, and anthropometry) by assigning scores of 0 to 4 to categories of each factor, for which higher values indicate healthier behaviors. Hazard ratios (HR) were estimated by Cox proportional regression and population attributable fractions (PAFs) estimated from the adjusted models. There was a 5% lower risk (adjusted HR 0.952, 95% confidence interval (CI): 0.946, 0.958) of all cancers per point score of the index for men and 4% (adjusted HR 0.961, 95% CI: 0.956, 0.966) for women. The fourth versus the second category of the HLIS was associated with a 28% and 24% lower risk for men and women respectively across all cancers, 41% and 33% for alcohol-related, 49% and 46% for tobacco-related, 41% and 26% for obesity-related, and 21% for female reproductive cancers. Findings suggest simple behavior modifications could have a sizeable impact on cancer prevention, especially for men.
Epidemiologic studies examining the association between specific fatty acids and colorectal cancer (CRC) risk are inconclusive. We investigated the association between dietary estimates and plasma ...levels of individual and total saturated (SFA), monounsaturated (MUFA), industrial‐processed trans (iTFA), and ruminant‐sourced trans (rTFA) fatty acids, and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Baseline fatty acid intakes were estimated in 450 112 participants (6162 developed CRC, median follow‐up = 15 years). In a nested case‐control study, plasma phospholipid fatty acids were determined by gas chromatography in 433 colon cancer cases and 433 matched controls. Multivariable‐adjusted hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were computed using Cox and conditional logistic regression, respectively. Dietary total SFA (highest vs lowest quintile, HRQ5vsQ1 = 0.80; 95%CI:0.69‐0.92), myristic acid (HRQ5vsQ1 = 0.83, 95%CI:0.74‐0.93) and palmitic acid (HRQ5vsQ1 = 0.81, 95%CI:0.70‐0.93) were inversely associated with CRC risk. Plasma myristic acid was also inversely associated with colon cancer risk (highest vs lowest quartile, ORQ4vsQ1 = 0.51; 95%CI:0.32‐0.83), whereas a borderline positive association was found for plasma stearic acid (ORQ4vsQ1 = 1.63; 95%CI:1.00‐2.64). Dietary total MUFA was inversely associated with colon cancer (per 1‐SD increment, HR1‐SD = 0.92, 95%CI: 0.85‐0.98), but not rectal cancer (HR1‐SD = 1.04, 95%CI:0.95‐1.15, Pheterogeneity = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR1‐SD = 1.07, 95%CI:1.02‐1.13). Our results suggest that total and individual saturated fatty acids and fatty acids of industrial origin may be relevant to the aetiology of CRC. Both dietary and plasma myristic acid levels were inversely associated with colon cancer risk, which warrants further investigation.
What's new?
The role of specific fatty acids in cancer development is not fully understood. In this large, prospective European study of colorectal cancer (CRC) risk, the authors found that dietary myristic and palmitic acids from dairy were inversely associated with CRC risk, as were total saturated (SFA) and monounsaturated (MUFA) fatty acids. Dietary industrially‐processed trans fatty acids (iTFA) were positively associated with rectal cancer. These results suggest that total and individual saturated fatty acids may be relevant to the aetiology of CRC.
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