Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite ...profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow‐up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.
What's new?
This prospective study is the largest investigation of metabolite profile and prostate cancer risk, to date. We found that patterns in plasma metabolite profile (characterized by higher concentrations of phosphatidylcholines and hydroxysphingomyelins; specific acylcarnitines, amino acids and a biogenic amine; and lysophosphatidylcholines, respectively) were associated with subsequent lower risk of more aggressive tumor subtypes and prostate cancer death. Moreover, the results suggest that metabolite profile may be relevant to the etiology of advanced stage disease.
Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated ...with increased mortality after CRC diagnosis. We examined pre‐diagnostic serum resistin concentrations in relation to CRC‐specific and all‐cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC‐specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause‐specific Cox proportional hazards models and further in sensitivity analyses using Fine–Gray proportional subdistribution hazards models. For all‐cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow‐up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC‐specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73–1.23; Ptrend = .97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84–1.19; P = .98) or all‐cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre‐diagnostic circulating resistin concentrations and CRC‐specific or all‐cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.
What's new?
Previous studies suggested that obesity and inflammation are related to cancer progression, and resistin was proposed as an obesity biomarker involved in inflammatory processes in humans. However, it remained unclear whether resistin is associated with increased mortality after colorectal cancer diagnosis. In this study the authors examined the novel association between pre‐diagnostic level of resistin and mortality in 1343 incident colorectal cancer patients. Resistin concentrations measured 4.8 years before diagnosis were not associated with mortality in individuals with CRC. These findings do not support the hypothesis that resistin may contribute to cancer progression.
Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one‐third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well‐established ...characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa‐miR‐16‐5p, hsa‐miR‐29a‐3p, hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐223‐3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25–p75: 7–13 years). Overall, the upregulation of hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐29a‐3p was associated with subsequent risk of CLL OR1∆Ct‐unit increase (95%CI) = 1.42 (1.18–1.72), 1.64 (1.31–2.04) and 1.75 (1.31–2.34) for hsa‐miR‐150‐5p, hsa‐miR‐155‐5p and hsa‐miR‐29a‐3p, respectively and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve <0.62). hsa‐miR‐16‐5p and hsa‐miR‐223‐3p levels were unrelated to CLL risk. The findings of this first prospective study suggest that hsa‐miR‐29a, hsa‐miR‐150‐5p and hsa‐miR‐155‐5p were upregulated in early stages of CLL but were modest predictive biomarkers of CLL risk.
What's new?
Aberrant circulating microRNA (miRNA) levels are a well‐established characteristic of chronic lymphocytic leukemia (CLL), but pre‐diagnosis data remain scarce. In this nested case–control study within the European Prospective Investigation into Cancer and Nutrition Study, circulating hsa‐miRNA‐29a‐3p, ‐150‐5p, and ‐155‐5p were upregulated up to 10 years before CLL diagnosis compared to controls, suggesting a role in early disease progression. However, these biomarkers were suboptimal to discriminate CLL from controls. No difference was observed in hsa‐miRNA‐16‐5p and ‐223‐3p expression between pre‐CLL and controls. The ability to detect pre‐clinical biomarkers may help better understand CLL development and open new avenues for personalized treatment.
A substantial proportion of epithelial ovarian cancer (EOC) arises in the fallopian tube and other epithelia of the upper genital tract; these epithelia may incur damage and neoplastic transformation ...after sexually transmitted infections (STI) and pelvic inflammatory disease. We investigated the hypothesis that past STI infection, particularly Chlamydia trachomatis, is associated with higher EOC risk in a nested case‐control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort including 791 cases and 1669 matched controls. Serum antibodies against C. trachomatis, Mycoplasma genitalium, herpes simplex virus type 2 (HSV‐2) and human papillomavirus (HPV) 16, 18 and 45 were assessed using multiplex fluorescent bead‐based serology. Conditional logistic regression was used to estimate relative risks (RR) and 95% confidence intervals (CI) comparing women with positive vs. negative serology. A total of 40% of the study population was seropositive to at least one STI. Positive serology to C. trachomatis Pgp3 antibodies was not associated with EOC risk overall, but with higher risk of the mucinous histotype (RR = 2.30 95% CI = 1.22‐4.32). Positive serology for chlamydia heat shock protein 60 (cHSP60‐1) was associated with higher risk of EOC overall (1.36 1.13‐1.64) and with the serous subtype (1.44 1.12‐1.85). None of the other evaluated STIs were associated with EOC risk overall; however, HSV‐2 was associated with higher risk of endometrioid EOC (2.35 1.24‐4.43). The findings of our study suggest a potential role of C. trachomatis in the carcinogenesis of serous and mucinous EOC, while HSV‐2 might promote the development of endometrioid disease.
What's new?
Sexually transmitted infections (STI) have been linked with pelvic inflammatory disease but their association with ovarian cancer remains unclear. In this large prospective study, serum antibodies against Chlamydia trachomatis were associated with higher epithelial ovarian cancer risk, though some associations were limited to select histotypes. Herpes simplex virus type 2 infection was associated with endometrioid ovarian cancer, a rarer ovarian cancer subtype. These findings underscore that STIs may be important in the etiology of ovarian cancer and may represent a target for primary prevention.
The European Prospective Investigation into Cancer and Nutrition (EPIC) is a multicentre prospective study conducted in 23 centres in 10 European countries. Here we review the findings from EPIC on ...the relationship between diet-related exposures and incidence or mortality from the four most frequent cancers in the European population: colorectal, breast, lung, and prostate cancer. We conducted a systematic review following PRISMA guidelines and identified 110 high-quality studies based on the EPIC cohort. Fruit and vegetable consumption had a protective effect against colorectal, breast, and lung cancer, whereas only fruit had a protective effect against prostate cancer. A higher consumption of fish and lower consumption of red and processed meat were related with a lower risk of colorectal cancer; and higher consumption of fatty fish with lower risk of breast cancer. Calcium and yogurt intake were found to protect against colorectal and prostate cancer. Alcohol consumption increased the risk for colorectal and breast cancer. Finally, adherence to the Mediterranean diet emerged as a protective factor for colorectal and breast cancer. The EPIC study results are in agreement with the latest evidence from leading authorities on cancer prevention and help to inform public prevention policies and strategies.
Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation ...to colorectal cancer screening implementation in European countries.
Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed.
In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from −2·5% (95% CI −2·8 to −2·2) to −1·6% (−2·0 to −1·2) in men and from −2·4% (−2·7 to −2·1) to −1·3% (−1·7 to −0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from −0·2% (95% CI −1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from −0·5% (−1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes.
We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation.
German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.
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.
What's new?
Malignant pleural mesothelioma (MPM), though rare, is an aggressive cancer chiefly caused by exposure to asbestos. Here, the authors describe a distinctive DNA methylation profile that can help clinicians identify people who are at higher risk of developing MPM. Using samples from 135 individuals who developed MPM and 135 cancer‐free controls, they identified nine sites that had methylation differences between the cancer cases and the controls. This biomarker profile could help screen asbestos‐exposed individuals for MPM and improve early detection.
The associations of individual dietary fatty acids with prostate cancer risk have not been examined comprehensively. We examined the prospective association of individual dietary fatty acids with ...prostate cancer risk overall, by tumor subtypes, and prostate cancer death. 142,239 men from the European Prospective Investigation into Cancer and Nutrition who were free from cancer at recruitment were included. Dietary intakes of individual fatty acids were estimated using center‐specific validated dietary questionnaires at baseline and calibrated with 24‐h recalls. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average follow‐up of 13.9 years, 7,036 prostate cancer cases and 936 prostate cancer deaths were ascertained. Intakes of individual fatty acids were not related to overall prostate cancer risk. There was evidence of heterogeneity in the association of some short chain saturated fatty acids with prostate cancer risk by tumor stage (pheterogeneity < 0.015), with a positive association with risk of advanced stage disease for butyric acid (4:0; HR1SD = 1.08; 95%CI = 1.01–1.15; p‐trend = 0.026). There were no associations with fatal prostate cancer, with the exception of a slightly higher risk for those who consumed more eicosenoic acid (22:1n‐9c; HR1SD = 1.05; 1.00–1.11; p‐trend = 0.048) and eicosapentaenoic acid (20:5n‐3c; HR1SD = 1.07; 1.00–1.14; p‐trend = 0.045). There was no evidence that dietary intakes of individual fatty acids were associated with overall prostate cancer risk. However, a higher intake of butyric acid might be associated with a higher risk of advanced, whereas intakes of eicosenoic and eicosapentaenoic acids might be positively associated with fatal prostate cancer risk.
What's new?
Are individual dietary fatty acids associated with prostate cancer development and progression? In this large, prospective study, the authors found that for prostate cancer overall, the answer is no. However, a higher intake of butyric acid may be associated with an increased risk of advanced‐stage prostate cancer, and higher intakes of eicosenoic and eicosapentaenoic acids may be positively associated with risk of lethal prostate cancer.
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.
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.
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.
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.
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