Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35-70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). RESULTS: After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. CONCLUSIONS: Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

Combining Advanced Analytical Methodologies to Uncover Suspect PFAS and Fluorinated Pharmaceutical Contributions to Extractable Organic Fluorine in Human Serum (Tromsø Study).

A growing number of studies have reported that routinely monitored per- and polyfluoroalkyl substances (PFAS) are not sufficient to explain the extractable organic fluorine (EOF) measured in human blood. In this study, we address this gap by screening pooled human serum collected over 3 decades (1986-2015) in Tromsø (Norway) for >5000 PFAS and >300 fluorinated pharmaceuticals. We combined multiple analytical techniques (direct infusion Fourier transform ion cyclotron resonance mass spectrometry, liquid chromatography-Orbitrap-high-resolution mass spectrometry, and total oxidizable precursors assay) in a three-step suspect screening process which aimed at unequivocal suspect identification. This approach uncovered the presence of one PFAS and eight fluorinated pharmaceuticals (including some metabolites) in human serum. While the PFAS suspect only accounted for 2-4% of the EOF, fluorinated pharmaceuticals accounted for 0-63% of the EOF, and their contribution increased in recent years. Although fluorinated pharmaceuticals often contain only 1-3 fluorine atoms, our results indicate that they can contribute significantly to the EOF. Indeed, the contribution from fluorinated pharmaceuticals allowed us to close the organofluorine mass balance in pooled serum from 2015, indicating a good understanding of organofluorine compounds in humans. However, a portion of the EOF in human serum from 1986 and 2007 still remained unexplained.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Assessment of the EarlyCDT-Lung test as an early biomarker of lung cancer in ever-smokers: A retrospective nested case-control study in two prospective cohorts.

The EarlyCDT-Lung test is a blood-based autoantibody assay intended to identify high-risk individuals for low-dose computed tomography lung cancer screening. However, there is a paucity of evidence on the performance of the EarlyCDT-Lung test in ever-smokers. We conducted a nested case-control study within two prospective cohorts to evaluate the risk-discriminatory performance of the EarlyCDT-Lung test using prediagnostic blood samples from 154 future lung cancer cases and 154 matched controls. Cases were selected from those who had ever smoked and had a prediagnostic blood sample <3 years prior to diagnosis. Conditional logistic regression was used to estimate the association between EarlyCDT-Lung test results and lung cancer risk. Sensitivity and specificity of the EarlyCDT-Lung test were calculated in all subjects and subgroups based on age, smoking history, lung cancer stage, sample collection time before diagnosis and year of sample collection. The overall lung cancer odds ratios were 0.89 (95% CI: 0.34-2.30) for a moderate risk EarlyCDT-Lung test result and 1.09 (95% CI: 0.48-2.47) for a high-risk test result compared to no significant test result. The overall sensitivity was 8.4% (95% CI: 4.6-14) and overall specificity was 92% (95% CI: 87-96) when considering a high-risk result as positive. Stratified analysis indicated higher sensitivity (17%, 95% CI: 7.2-32.1) in subjects with blood drawn up to 1 year prior to diagnosis. In conclusion, our study does not support a role of the EarlyCDT-Lung test in identifying the high-risk subjects in ever-smokers for lung cancer screening in the EPIC and NSHDS cohorts.

Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: The EPIC prospective cohort.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive noninvasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM prediagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow-up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within 5 years from enrolment (n = 36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex and PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than 5 years before diagnosis (area under the curve [AUC] < 5 years = 0.89; AUC 5-10 years = 0.80; AUC >10 years = 0.75; baseline AUC range = 0.63-0.67). DNAm changes as noninvasive biomarkers in prediagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk to possibly adopt more intensive monitoring for early disease identification.

Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients.

Glyceraldehyde-derived advanced glycation end products (glycer-AGEs) could contribute to colorectal cancer development and progression due to their pro-oxidative and pro-inflammatory properties. However, the association of glycer-AGEs with mortality after colorectal cancer diagnosis has not been previously investigated. Circulating glycer-AGEs were measured by competitive ELISA. Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for associations of circulating glycer-AGEs concentrations with CRC-specific and all-cause mortality among 1034 colorectal cancer (CRC) cases identified within the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1993 and 2013. During a mean of 48 months of follow-up, 529 participants died (409 from CRC). Glycer-AGEs were statistically significantly positively associated with CRC-specific (HRQ5 vs Q1  = 1.53, 95% CI: 1.04-2.25, Ptrend  = .002) and all-cause (HRQ5 vs Q1  = 1.62, 95% CI: 1.16-2.26, Ptrend  < .001) mortality among individuals with CRC. There was suggestion of a stronger association between glycer-AGEs and CRC-specific mortality among patients with distal colon cancer (per SD increment: HRproximal colon  = 1.02, 95% CI: 0.74-1.42; HRdistal colon  = 1.51, 95% CI: 1.20-1.91; Peffect modification  = .02). The highest HR was observed among CRC cases in the highest body mass index (BMI) and glycer-AGEs category relative to lowest BMI and glycer-AGEs category for both CRC-specific (HR = 1.78, 95% CI: 1.02-3.01) and all-cause mortality (HR = 2.15, 95% CI: 1.33-3.47), although no statistically significant effect modification was observed. Our study found that prediagnostic circulating glycer-AGEs are positively associated with CRC-specific and all-cause mortality among individuals with CRC. Further investigations in other populations and stratifying by tumor location and BMI are warranted.

Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition.

INTRODUCTION: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort. METHODS: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile. DISCUSSION: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts.

BACKGROUND: Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS: Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. RESULTS: Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. CONCLUSIONS: Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.

Fluorine Mass Balance, including Total Fluorine, Extractable Organic Fluorine, Oxidizable Precursors, and Target Per- and Polyfluoroalkyl Substances, in Pooled Human Serum from the Tromsø Population in 1986, 2007, and 2015.

Of the thousands of per- and polyfluoroalkyl substances (PFAS) known to exist, only a small fraction (≤1%) are commonly monitored in humans. This discrepancy has led to concerns that human exposure may be underestimated. Here, we address this problem by applying a comprehensive fluorine mass balance (FMB) approach, including total fluorine (TF), extractable organic fluorine (EOF), total oxidizable precursors (TOP), and selected target PFAS, to human serum samples collected over a period of 28 years (1986, 2007, and 2015) in Tromsø, Norway. While concentrations of TF did not change between sampling years, EOF was significantly higher in 1986 compared to 2007 and 2015. The ∑12PFAS concentrations were highest in 2007 compared to 1986 and 2015, and unidentified EOF (UEOF) decreased from 1986 (46%) to 2007 (10%) and then increased in 2015 (37%). While TF and EOF were not influenced by sex, women had higher UEOF compared to men, opposite to target PFAS. This is the first FMB in human serum to include TOP, and it suggests that precursors with >4 perfluorinated carbon atoms make a minor contribution to EOF (0-4%). Additional tools are therefore needed to identify substances contributing to the UEOF in human serum.

Nevus Count, Pigmentary Characteristics, and Melanoma-specific Mortality among Norwegian Women with Melanoma >1.0 mm Thick.

Little is known about if and how nevi and pigmentation are associated with melanoma-specific mortality. However, increased melanoma awareness in people with lighter pigmentation and many nevi may result in earlier diagnosis of thinner less-lethal tumors. The aim of this study was to investigate associations between nevus count (asymmetrical > 5 mm and small symmetrical), pigmentary characteristics (hair colour, eye colour, skin colour, freckling, pigmentary score), and melanoma-specific mortality in subjects with melanomas > 1 mm. Data from the Norwegian Women and Cancer cohort, established in 1991, with complete follow-up of melanoma patients until 2018 through the Cancer Registry of Norway, were used to estimate hazard ratios with 95% confidence intervals for the associations between nevus count, pigmentary characteristics, and melanoma-specific mortality, stratified by tumor thickness using Cox regression. Estimated hazard ratios consistently indicated a higher risk of melanoma death for those with darker vs lighter pigmentary characteristics in patients with tumors > 1.0-2.0 mm and > 2.0 mm thick (e.g. pigmentary score hazard ratio 1.25, 95% confidence interval (0.74-2.13)). Among women with melanomas > 1.0 mm thick, lighter pigmentation and asymmetrical nevi may be associated with lower melanoma-specific mortality, suggesting that factors that increase the risk of melanoma may also be associated with decreased risk of death from melanoma.

Overall lifestyle changes in adulthood are associated with cancer incidence in the Norwegian Women and Cancer Study (NOWAC) - a prospective cohort study.

BACKGROUND: Cancer is a leading cause of premature death worldwide and incidence is expected to rise in the coming decades. Many cohort studies, measuring lifestyle factors at one time-point, have observed that overall healthy lifestyles were inversely related to cancer incidence. However, there is little knowledge on the impact of lifestyle modification within adulthood. METHODS: Using the Norwegian Women and Cancer study, two repeated self-reported assessments of lifestyle behaviours were used to calculate healthy lifestyle index scores at each time-point (N = 66 233). The associations between change in healthy lifestyle index score and lifestyle-related cancer incidence, including alcohol-, tobacco-, obesity-, and reproductive-related, and site-specific breast and colorectal cancer incidence were estimated using Cox proportional hazard regression models. To assess nonlinearity in the dose-response relationships, restricted cubic spline models were used. RESULTS: Independent of baseline lifestyle, positive lifestyle changes were inversely related to the incidence of overall lifestyle-related cancers, as well as alcohol-related, tobacco-related, obesity-related, and reproductive-related cancers, but not breast and colorectal site-specific cancers. An association between lifestyle worsening and cancer incidence compared to stable lifestyle was observed. CONCLUSIONS: This study provides evidence that overall lifestyle changes among cancer-free women between the ages of 41 and 76 impact the incidence of many cancer types. Regardless of baseline lifestyle, there was a negative dose-response relationship between magnitude of positive lifestyle change and the incidence of overall lifestyle-related cancers. We observed that underlying this trend was an especially clear association between lifestyle worsening and increased risk compared to stable lifestyle. For adult women, maintaining a stable healthy lifestyle and lifestyle improvement are important for preventing the occurrence of many cancer types.

Diet-wide association study of 92 foods and nutrients and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition study and the Netherlands Cohort Study.

It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327 790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per SD higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day = 0.91, 95% CI 0.87-0.96), fruit (HR = 0.91, 95% CI 0.86-0.96) and vitamin C (HR = 0.91, 95% CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR = 1.08, 95% CI 1.03-1.14), retinol (HR = 1.06, 95% CI 1.03-1.10) and beer/cider (HR = 1.04, 95% CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer.

Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCS) exhibit significantly increased chronic diseases and premature death. Abnormalities in DNA methylation are associated with development of chronic diseases and reduced life expectancy. We investigated the hypothesis that anti-cancer treatments are associated with long-term DNA methylation changes that could be key drivers of adverse late health effects. METHODS: Genome-wide DNA methylation was assessed using MethylationEPIC arrays in paired samples (before/after therapy) from 32 childhood cancer patients. Separately, methylation was determined in 32 samples from different adult CCS (mean 22-years post-diagnosis) and compared with cancer-free controls (n = 284). RESULTS: Widespread DNA methylation changes were identified post-treatment in childhood cancer patients, including 146 differentially methylated regions (DMRs), which were consistently altered in the 32 post-treatment samples. Analysis of adult CCS identified matching methylation changes at 107/146 of the DMRs, suggesting potential long-term retention of post-therapy changes. Adult survivors also exhibited epigenetic age acceleration, independent of DMR methylation. Furthermore, altered methylation at the DUSP6 DMR was significantly associated with early mortality, suggesting altered methylation may be prognostic for some late adverse health effects in CCS. CONCLUSIONS: These novel methylation changes could serve as biomarkers for assessing normal cell toxicity in ongoing treatments and predicting long-term health outcomes in CCS.

Prospective evaluation of 92 serum protein biomarkers for early detection of ovarian cancer.

BACKGROUND: CA125 is the best available yet insufficiently sensitive biomarker for early detection of ovarian cancer. There is a need to identify novel biomarkers, which individually or in combination with CA125 can achieve adequate sensitivity and specificity for the detection of earlier-stage ovarian cancer. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we measured serum levels of 92 preselected proteins for 91 women who had blood sampled ≤18 months prior to ovarian cancer diagnosis, and 182 matched controls. We evaluated the discriminatory performance of the proteins as potential early diagnostic biomarkers of ovarian cancer. RESULTS: Nine of the 92 markers; CA125, HE4, FOLR1, KLK11, WISP1, MDK, CXCL13, MSLN and ADAM8 showed an area under the ROC curve (AUC) of ≥0.70 for discriminating between women diagnosed with ovarian cancer and women who remained cancer-free. All, except ADAM8, had shown at least equal discrimination in previous case-control comparisons. The discrimination of the biomarkers, however, was low for the lag-time of >9-18 months and paired combinations of CA125 with any of the 8 markers did not improve discrimination compared to CA125 alone. CONCLUSION: Using pre-diagnostic serum samples, this study identified markers with good discrimination for the lag-time of 0-9 months. However, the discrimination was low in blood samples collected more than 9 months prior to diagnosis, and none of the markers showed major improvement in discrimination when added to CA125.

Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort.

BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression. RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants. CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.

Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations. METHODS: We analysed targeted metabolomics data available for 5828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data-shared lasso penalty. RESULTS: Out of the 50 studied metabolites, (i) six were inversely associated with the risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2, and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine, and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk. CONCLUSIONS: These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.

Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking.

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.

Longitudinal changes in concentrations of persistent organic pollutants (1986-2016) and their associations with type 2 diabetes mellitus.

BACKGROUND: Positive associations have been reported between persistent organic pollutants (POPs) and type 2 diabetes mellitus (T2DM); however, causality has not been established. Over the last decades, environmental exposure to legacy POPs has decreased, complicating epidemiological studies. In addition, physiological risk factors for T2DM may also influence POP concentrations, contributing to a complex network of factors that could impact associations with T2DM. Longitudinal studies on this topic are lacking, and few have assessed prospective and cross-sectional associations between repeated POP measurements and T2DM in the same individuals, which may shed light on causality. OBJECTIVES: To compare longitudinal trends in concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in T2DM cases and controls, and to examine prospective and cross-sectional associations between PCBs, OCPs and T2DM at different time-points before and after T2DM diagnosis in cases. METHODS: We conducted a longitudinal, nested case-control study (1986-2016) of 116 T2DM cases and 139 controls from the Tromsø Study. All participants had three blood samples collected before T2DM diagnosis in cases, and up to two samples thereafter. We used linear mixed-effect models to assess temporal changes of POPs within and between T2DM cases and controls, and logistic regression models to investigate the associations between different POPs and T2DM at different time-points. RESULTS: PCBs, trans-nonachlor, cis-nonachlor, oxychlordane, cis-heptachlor epoxide, p,p'-DDE, and p,p'-DDT declined more slowly in cases than controls, whereas ß-HCH and HCB declined similarly in both groups. Most POPs showed positive associations between both pre- and post-diagnostic concentrations and T2DM, though effect estimates were imprecise. These associations were most consistent for cis-heptachlor epoxide. DISCUSSION: The observed positive associations between certain POPs and T2DM may be because of higher POP concentrations within prospective T2DM cases, due to slower temporal declines as compared to controls.

Seroprevalence of antibodies against SARS-CoV-2 in the adult population during the pre-vaccination period, Norway, winter 2020/21.

BackgroundSince March 2020, 440 million people worldwide have been diagnosed with COVID-19, but the true number of infections with SARS-CoV-2 is higher. SARS-CoV-2 antibody seroprevalence can add crucial epidemiological information about population infection dynamics.AimTo provide a large population-based SARS-CoV-2 seroprevalence survey from Norway; we estimated SARS-CoV-2 seroprevalence before introduction of vaccines and described its distribution across demographic groups.MethodsIn this population-based cross-sectional study, a total of 110,000 people aged 16 years or older were randomly selected during November-December 2020 and invited to complete a questionnaire and provide a dried blood spot (DBS) sample.ResultsThe response rate was 30% (31,458/104,637); compliance rate for return of DBS samples was 88% (27,700/31,458). National weighted and adjusted seroprevalence was 0.9% (95% CI (confidence interval): 0.7-1.0). Seroprevalence was highest among those aged 16-19 years (1.9%; 95% CI: 0.9-2.9), those born outside the Nordic countries 1.4% (95% CI: 1.0-1.9), and in the counties of Oslo 1.7% (95% CI: 1.2-2.2) and Vestland 1.4% (95% CI: 0.9-1.8). The ratio of SARS-CoV-2 seroprevalence (0.9%) to cumulative incidence of virologically detected cases by mid-December 2020 (0.8%) was slightly above one. SARS-CoV-2 seroprevalence was low before introduction of vaccines in Norway and was comparable to virologically detected cases, indicating that most cases in the first 10 months of the pandemic were detected.ConclusionFindings suggest that preventive measures including contact tracing have been effective, people complied with physical distancing recommendations, and local efforts to contain outbreaks have been essential.

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs-Nε-(carboxy-methyl)lysine (CML), Nε-(carboxy-ethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)-were measured by ultra-performance liquid chromatography-tandem mass spectrometry in baseline samples collected from 1378 incident primary colorectal cancer cases and 1378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5 versus Q1 = 0.40, 95% CI: 0.27-0.59), MG-H1 (ORQ5 versus Q1 = 0.73, 95% CI: 0.53-1.00) and total AGEs (OR Q5 versus Q1 = 0.52, 95% CI: 0.37-0.73), whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5 versus Q1 = 1.91, 95% CI: 1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical sub-site. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.