Publications by authors named "Rosario Tumino"

767 Publications

Plasma concentrations of persistent organic pollutants and pancreatic cancer risk.

Int J Epidemiol 2021 Jul 14. Epub 2021 Jul 14.

Cancer Registry and Histopathology Department, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.

Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.

Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.

Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.

Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.
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http://dx.doi.org/10.1093/ije/dyab115DOI Listing
July 2021

Factors associated with serum ferritin levels and iron excess: results from the EPIC-EurGast study.

Eur J Nutr 2021 Jul 2. Epub 2021 Jul 2.

Unit of Nutrition and Cancer, Catalan Institute of Oncology - ICO, Nutrition and Cancer Group, Bellvitge Biomedical Research Institute -(IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Purpose: Excess iron is involved in the development of non-communicable diseases such as cancer, type 2 diabetes and cardiovascular conditions. We aimed to describe the prevalence of excess iron and its determinants in healthy European adults.

Methods: Sociodemographic, lifestyle, iron status, dietary information, and HFE genotyping were obtained from controls from the nested case-control study EPIC-EurGast study. High sensitivity C-reactive protein (hsCRP) was measured to address possible systemic inflammation. Descriptive and multivariate analyses were used to assess iron status and its determinants.

Results: Out of the 828 participants (median age: 58.7 years), 43% were females. Median serum ferritin and prevalence of excess iron were 143.7 µg/L and 35.2% in males, respectively, and 77 µg/L and 20% in females, both increasing with latitude across Europe. Prevalence of HFE C282Y mutation was significantly higher in Northern and Central Europe (~ 11%) than in the South (5%). Overweight/obesity, age, and daily alcohol and heme iron intake were independent determinants for iron status, with sex differences even after excluding participants with hsCRP > 5 mg/L. Obese males showed a greater consumption of alcohol, total and red meat, and heme iron, compared with those normal weight.

Conclusion: Obesity, higher alcohol and heme iron consumption were the main risk factors for excess iron in males while only age was associated with iron overload in females. Weight control and promoting healthy lifestyle may help prevent iron overload, especially in obese people. Further research is needed to clarify determinants of excess iron in the healthy adult population, helping to reduce the associated comorbidities.
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http://dx.doi.org/10.1007/s00394-021-02625-wDOI Listing
July 2021

Inflammatory potential of the diet and risk of breast cancer in the European Investigation into Cancer and Nutrition (EPIC) study.

Eur J Epidemiol 2021 Jun 20. Epub 2021 Jun 20.

Director Office, International Agency for Research on Cancer, World Health Organization, Lyon, France.

The role of chronic inflammation on breast cancer (BC) risk remains unclear beyond as an underlying mechanism of obesity and physical activity. We aimed to evaluate the association between the inflammatory potential of the diet and risk of BC overall, according to menopausal status and tumour subtypes. Within the European Prospective Investigation into Cancer and Nutrition cohort, 318,686 women were followed for 14 years, among whom 13,246 incident BC cases were identified. The inflammatory potential of the diet was characterized by an inflammatory score of the diet (ISD). Multivariable Cox regression models were used to assess the potential effect of the ISD on BC risk by means of hazard ratios (HR) and 95% confidence intervals (CI). ISD was positively associated with BC risk. Each increase of one standard deviation (1-Sd) of the score increased by 4% the risk of BC (HR = 1.04; 95% CI 1.01-1.07). Women in the highest quintile of the ISD (indicating a most pro-inflammatory diet) had a 12% increase in risk compared with those in the lowest quintile (HR = 1.12; 95% CI 1.04-1.21) with a significant trend. The association was strongest among premenopausal women, with an 8% increased risk for 1-Sd increase in the score (HR = 1.08; 95% CI 1.01-1.14). The pattern of the association was quite homogeneous by BC subtypes based on hormone receptor status. There were no significant interactions between ISD and body mass index, physical activity, or alcohol consumption. Women consuming more pro-inflammatory diets as measured by ISD are at increased risk for BC, especially premenopausal women.
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http://dx.doi.org/10.1007/s10654-021-00772-2DOI Listing
June 2021

Mortality temporal trends and cancer incidence profiles of residents in the petrochemical industrially contaminated town of Gela (Sicily, Italy).

Ann Ist Super Sanita 2021 Apr-Jun;57(2):174-182

Dipartimento Ambiente e Salute, Istituto Superiore di Sanità, Rome, Italy - WHO Collaborating Centre for Environmental Health in Contaminated Sites, Istituto Superiore di Sanità, Rome, Italy.

Objective: In 2000, a vast area in Gela (Sicily, Italy) was defined as a national priority contaminated site due to pollution from a petrochemical complex. This study is aimed at addressing the influence of the petrochemical complex on the health profile of residents in Gela.

Methods: Trend analysis by gender was performed for mortality for all diseases and malignant cancers, in the period 1980-2014 for residents in the municipality of Gela, by directly standardized rates and Joinpoint regressions, using, as a reference population, people resident in the Sicily region. SMRs were computed for 5-year periods in the same timespan. Since the beginning of the period analyzed, the share of population of Gela represents 1.5% of total residents in Sicily. Cancer incidence was analyzed for the period 2007-2012 applying a hierarchical Bayesian model to estimate Standardized Incidence Ratios (SIR). Ranks of these ratios were computed to highlight the most incident diseases affecting the population. Malignant neoplasms of lung, stomach and colon were selected because of a priori interest, as they are associated, in etiological terms, with the main contaminants found in the area. Malignant neoplasms of liver, pancreas and larynx were selected as "control diseases" since they share the same main risk factors (smoke and alcohol consumption) of neoplasms of a priori interest, but are not associated with the priority index contaminants identified in Gela.

Results: Mortality rates for all causes combined in both genders in Gela decreased over time, but they were higher than those of the whole Sicilian population. The trend of mortality rates due to all malignant cancers increased in men, especially from 1980 to 1987. This result was confirmed by the Joinpoint regression (annual percentage change (APC) 9.8). SMRs analysis showed significant excesses in mortality due to all diseases for both genders compared to the reference population. Other excesses were observed for mortality due to malignant cancers in men and for circulatory diseases in women. The trend for cancers in women in Gela increased from the mid-nineties but less than in men. SIR estimates were higher than 1 for all the diseases analyzed and in both sexes, and their ranks highlighted that cancer sites of a priori interest hold higher positions than "control diseases", although credibility intervals overlapped.

Conclusions: Results highlight that the health profile of residents in Gela is worse than the one of the reference population. Moreover, cancer incidence is in excess in all the sites analyzed and mortality due to all cancers combined has a trend compatible with a cumulative impact due to petrochemical contamination.
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http://dx.doi.org/10.4415/ANN_21_02_10DOI Listing
June 2021

Prospective analysis of circulating metabolites and endometrial cancer risk.

Gynecol Oncol 2021 Aug 5;162(2):475-481. Epub 2021 Jun 5.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.

Background: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed.

Results: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR: 0.89, 95% CI: 0.80-0.99; OR: 0.89, 95% CI: 0.79-1.00 and OR: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results.

Conclusion: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.
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http://dx.doi.org/10.1016/j.ygyno.2021.06.001DOI Listing
August 2021

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Nutrients 2021 May 28;13(6). Epub 2021 May 28.

Office of the Director, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France.

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
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http://dx.doi.org/10.3390/nu13061843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228096PMC
May 2021

Novel Biomarkers of Habitual Alcohol Intake and Associations with Risk of Pancreatic and Liver Cancers and Liver Disease Mortality.

J Natl Cancer Inst 2021 May 19. Epub 2021 May 19.

Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands.

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk.

Methods: Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies.

Results: Two metabolites displayed a dose-response association with self-reported alcohol intake 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54; 95% CI = 1.51-4.27) and pancreatic cancer (OR = 1.43; 95% CI = 1.03-1.99) in EPIC and liver cancer (OR = 2.00; 95% CI = 1.44-2.77) and liver disease mortality (OR = 2.16; 95% CI = 1.63-2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19; 95% CI = 1.60-2.98) in ATBC.

Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.
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http://dx.doi.org/10.1093/jnci/djab078DOI Listing
May 2021

Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Int J Cancer 2021 Apr 28. Epub 2021 Apr 28.

Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden.

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, HR  = 0.80; 95%CI:0.69-0.92), myristic acid (HR  = 0.83, 95%CI:0.74-0.93) and palmitic acid (HR  = 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, OR  = 0.51; 95%CI:0.32-0.83), whereas a borderline positive association was found for plasma stearic acid (OR  = 1.63; 95%CI:1.00-2.64). Dietary total MUFA was inversely associated with colon cancer (per 1-SD increment, HR  = 0.92, 95%CI: 0.85-0.98), but not rectal cancer (HR  = 1.04, 95%CI:0.95-1.15, P  = 0.027). Dietary iTFA, and particularly elaidic acid, was positively associated with rectal cancer (HR  = 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.
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http://dx.doi.org/10.1002/ijc.33615DOI Listing
April 2021

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

Clin Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk.

Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci.

Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons.

Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.
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http://dx.doi.org/10.1016/j.cgh.2021.04.028DOI Listing
April 2021

Dietary intake of advanced glycation endproducts and risk of hepatobiliary cancers: A multinational cohort study.

Int J Cancer 2021 Apr 25. Epub 2021 Apr 25.

Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, N -[carboxymethyl]lysine (CML), N -[1-carboxyethyl]lysine (CEL) and N -[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), was estimated using country-specific dietary questionnaires linked to an AGEs database. Cause-specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow-up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR-  = 0.87, 95% CI: 0.76-0.99, HR-  = 0.84, 95% CI: 0.74-0.96 and HR-  = 0.84, 95% CI: 0.74-0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR-  = 1.28, 95% CI: 1.05-1.56, HR-  = 1.17; 95% CI: 0.96-1.40, HR-  = 1.27, 95% CI: 1.06-1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer.
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http://dx.doi.org/10.1002/ijc.33612DOI Listing
April 2021

Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort.

Gut Microbes 2021 Jan-Dec;13(1):1-14

Department of Medical Biosciences, Pathology, Umeå University, Ireland.

Experimental evidence has implicated genotoxic () and enterotoxigenic (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to and ETBF with CRC.The IgA-positivity of any of the tested antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (= 0.095). Sero-positivity to and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.
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http://dx.doi.org/10.1080/19490976.2021.1903825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078709PMC
April 2021

Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition.

Cancer Epidemiol Biomarkers Prev 2021 Jun 13;30(6):1270-1274. Epub 2021 Apr 13.

International Agency for Research on Cancer (IARC-WHO), Lyon, France.

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.

Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively).

Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.

Impact: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611361PMC
June 2021

Dietary intake of trans fatty acids and breast cancer risk in 9 European countries.

BMC Med 2021 Mar 30;19(1):81. Epub 2021 Mar 30.

Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted.

Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors.

Results: After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes.

Conclusions: These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations.
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http://dx.doi.org/10.1186/s12916-021-01952-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008592PMC
March 2021

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

Carcinogenesis 2021 May;42(5):705-713

Office of the Director, International Agency for Research on Cancer (IARC), Lyon, France.

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.
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http://dx.doi.org/10.1093/carcin/bgab026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162627PMC
May 2021

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2021 May 2;30(5):953-964. Epub 2021 Mar 2.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer.

Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls).

Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04-1.40; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68).

Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer.

Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1218DOI Listing
May 2021

Red Blood Cell Fatty Acids and Risk of Colorectal Cancer in The European Prospective Investigation into Cancer and Nutrition (EPIC).

Cancer Epidemiol Biomarkers Prev 2021 May 22;30(5):874-885. Epub 2021 Feb 22.

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Background: A growing body of evidence suggests that alterations of dietary fatty acid (FA) profiles are associated with colorectal cancer risk. However, data from large-scale epidemiologic studies using circulating FA measurements to objectively assess individual FA and FA categories are scarce.

Methods: We investigate the association between red blood cell (RBC) membrane FAs and risk of colorectal cancer in a case-control study nested within a large prospective cohort. After a median follow-up of 6.4 years, 1,069 incident colorectal cancer cases were identified and matched to 1,069 controls among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). The FA composition of RBC phospholipids (in mol%) was analyzed by gas chromatography, and their association with risk of colorectal cancer was estimated by multivariable adjusted conditional logistic regression models.

Results: After correction for multiple testing, subjects with higher concentrations of RBC stearic acid were at higher risk for colorectal cancer (OR = 1.23; 95% CI = 1.07-1.42, per 1 mol%). Conversely, colorectal cancer incidence decreased with increasing proportions of RBC n-3 PUFA, particularly eicosapentaenoic acid (0.75; 0.62-0.92, per 1 mol%). The findings for the n-6 PUFA arachidonic acid were inconsistent.

Conclusions: The positive association between prediagnostic RBC stearic acid and colorectal cancer reflects putative differences in FA intake and metabolism between cancer cases and matched controls, which deserve further investigation. The inverse relationship between EPA and colorectal cancer is in line with the repeatedly reported protective effect of fish consumption on colorectal cancer risk.

Impact: These findings add to the evidence on colorectal cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1426DOI Listing
May 2021

Pepper Alkaloids and Processed Meat Intake: Results from a Randomized Trial and the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort.

Mol Nutr Food Res 2021 04 2;65(7):e2001141. Epub 2021 Mar 2.

Nutrition and Metabolism Branch, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon, France.

Scope: Processed meat intake has been associated with adverse health outcomes. However, little is known about the type of processed meat more particularly responsible for these effects. This study aims to identify novel biomarkers for processed meat intake.

Methods And Results: In a controlled randomized cross-over dietary intervention study, 12 healthy volunteers consume different processed and non-processed meats for 3 consecutive days each. Metabolomics analyses are applied on post-intervention fasting blood and urine samples to identify discriminating molecular features of processed meat intake. Nine and five pepper alkaloid metabolites, including piperine, are identified as major discriminants of salami intake in urine and plasma, respectively. The associations with processed meat intake are tested for replication in a cross-sectional study (n = 418) embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Three of the serum metabolites including piperine are associated with habitual intake of sausages and to a lesser extent of total processed meat.

Conclusion: Pepper alkaloids are major discriminants of intake for sausages that contain high levels of pepper used as ingredient. Further work is needed to assess if pepper alkaloids in combination with other metabolites may serve as biomarkers of processed meat intake.
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http://dx.doi.org/10.1002/mnfr.202001141DOI Listing
April 2021

Prospective Identification of Elevated Circulating CDCP1 in Patients Years before Onset of Lung Cancer.

Cancer Res 2021 Jul 11;81(13):3738-3748. Epub 2021 Feb 11.

MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer-related dysregulation of CDCP1 expression years before diagnosis. SIGNIFICANCE: Prospective proteomics analyses reveal an association between increased levels of circulating CDCP1 and lung carcinogenesis irrespective of smoking and years before diagnosis, and integrating gene expression indicates potential underlying mechanisms..
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611235PMC
July 2021

Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies.

Int J Cancer 2021 Jun 22;148(11):2759-2773. Epub 2021 Feb 22.

Hellenic Health Foundation, Athens, Greece.

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (P = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.
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http://dx.doi.org/10.1002/ijc.33504DOI Listing
June 2021

Skin melanoma deaths within 1 or 3 years from diagnosis in Europe.

Int J Cancer 2021 Jun 1;148(12):2898-2905. Epub 2021 Feb 1.

Piedmont Cancer Registry, Turin, Italy.

The steep increase in incidence of cutaneous malignant melanoma in white populations mainly applies to thin lesions with good survival suggesting overdiagnosis. Based on population-based cancer registries (CRs), we have investigated changes in aggressive melanoma, selecting only cases who died within 1 or 3 years after diagnosis in 11 European countries between 1995 and 2012. Trends in fatal cases were analysed by period of diagnosis, sex, tumour thickness, histologic subtype of the lesion, tumour site and CR with a multivariate generalised linear mixed effects model, where geographical area was considered as a random effect. We collected data on 123 360 invasive melanomas, with 5133 fatal cases at 1 year (4%) and 12 330 (10%) at 3 years. The number of fatal cases showed a 16% decrease at 1 year and 8% at 3 years between the first (1995-2000) and the last (2007-2012) period. The highest proportion of fatal cases was seen for men, older age (≥65 years), thick lesions (>1 mm), nodular melanoma, melanoma on the trunk and for poorly documented cases, lacking information about thickness and histologic subtype. The mixed-effects model showed a remarkable variability among European countries. The majority of registries showed a decreasing trend in fatal cases, but a few registries showed an opposite pattern. Trends in fatal melanoma cases, highlighting real changes in risk not related to overdiagnosis, showed a decrease in most European countries, with a few exceptions. Stronger efforts for early detection could lead to a more efficient treatment of melanoma in general.
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http://dx.doi.org/10.1002/ijc.33479DOI Listing
June 2021

Mid-term trends and recent birth-cohort-dependent changes in incidence rates of cutaneous malignant melanoma in Italy.

Int J Cancer 2021 02 28;148(4):835-844. Epub 2020 Aug 28.

Romagna Cancer Registry, Romagna Cancer Institute, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Forlì, Italy.

In Oceania, North America and north-western Europe, after decades of increase, cutaneous malignant melanoma (CMM) rates began to stabilise or decline before 2000. Anecdotal evidence suggests that the reversal of the incidence trend is extending to southern Europe. To obtain a formal confirmation, this nationwide study from Italy investigated the incidence trends by birth cohort. Twenty-one local cancer registries covering a population of 15 814 455 provided incidence data for primary CMM registered between 1994 and 2013. Trends in age-standardised rates were analysed using joinpoint regression models and age-period-cohort models. Age-standardised incidence showed a consistent increase throughout the period (estimated annual percent change, 3.6 [95% confidence interval, 3.2-4.0] among men and 2.5 [2.0-3.1] among women). This pattern was confirmed by a sensitivity analysis with removal of low-risk populations of southern Italy. The rates, however, showed a stabilisation or a decrease in men and women aged below 35. Using the cohort of 1949-the median cohort with respect to the number of cases for both genders-as a reference, the incidence rate ratio increased for successive cohorts born until 1973 (women) and 1975 (men), and subsequently tended to decline. For the most recent cohorts in both genders, the risk of disease returned to the level of the cohort of 1949. The changes observed in the latest generations can be interpreted as the earliest manifestations of a birth-cohort-dependent incidence decrease. Our study adds to previous data indicating that the reversal of the long-term upward incidence trend of CMM is extending to southern Europe.
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http://dx.doi.org/10.1002/ijc.33259DOI Listing
February 2021

Development and validation of a lifestyle-based model for colorectal cancer risk prediction: the LiFeCRC score.

BMC Med 2021 Jan 4;19(1). Epub 2021 Jan 4.

Public Health Directorate, Asturias, Spain.

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population.

Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992-2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed.

Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell's C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264-0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084-0.575)).

Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level.
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http://dx.doi.org/10.1186/s12916-020-01826-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780676PMC
January 2021

Authors' response: Mezei et al's "Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis".

Scand J Work Environ Health 2021 Jan 7;47(1):87-89. Epub 2020 Jul 7.

Epidemiology Unit, Occupational and Environmental Medicine, Epidemiology and Hygiene Department, INAIL (Italian national workers compensation authority), Via Stefano Gradi 55, 00143 Rome, Italy. E-mail:

Mezei et al's letter (1) is an opportunity to provide more details about our study on pericardial and tunica vaginalis testis (TVT) mesothelioma (2), which is based on the Italian national mesothelioma registry (ReNaM): a surveillance system on mesothelioma, with individual asbestos exposure assessment. Incidence of pericardial mesothelioma has been estimated around 0.5 and 0.2 cases per 10 million person-years in men and women, respectively, and around 1 case for TVT mesothelioma. ReNaM collected 138 cases thanks to its long period of observation (1993-2015) and national coverage. Conducting a population-based case-control study with incidence-density sampling of controls across Italy and over a 23 year time-span should have been planned in 1993 and would have been beyond feasibility and ReNaM scope. We rather exploited two existing series of controls (3). The resulting incomplete time- and spatial matching of cases and controls is a limitation of our study and has been acknowledged in our article. The analysis of case-control studies can nevertheless be accomplished in logistic models accounting for the variables of interest, in both individually and frequency matched studies (4). Furthermore, analyses restricted to (i) regions with enrolled controls, (ii) cases with definite diagnosis, (iii) incidence period 2000-2015, and (iv) subjects born before 1950 have been provided in the manuscript, confirming the strength of the association with asbestos exposure (supplemental material tables S4-7). Following Mezei et al's suggestion, we performed further sensitivity analyses by restriction to regions with controls and fitting conditional regression models using risk-sets made of combinations of age and year of birth categories (5-year classes for both). We confirmed positive associations with occupational exposure to asbestos of pericardial mesothelioma, with odds ratios (OR) (adjusted for region) of 9.16 among women [95% confidence interval (CI) 0.56-150] and 5.63 (95% CI 1.02-31.0) among men; for TVT mesothelioma the OR was 7.70 (95% CI 2.89-20.5). Using risk sets of age categories and introducing year of birth (5-year categories) as a covariate (dummy variables) the OR were similar: OR (adjusted for region) of 9.17 among women (95% CI 0.56-150) and 5.76 (95% CI 1.07-31.0) among men; for TVT the OR was 9.86 (95% CI 3.46-28.1). Possible bias from incomplete geographical overlap between cases and controls has been addressed in the paper (table S4) and above. In spatially restricted analyses, OR were larger than in those including cases from the whole country, indicating that bias was towards the null. Mezei et al further noted that "the regional distribution of controls is different from that of person-time observed". This objection is not relevant because the above analyses were adjusted by region. Our controls were provided by a population-based study on pleural mesothelioma (called MISEM) and a hospital-based study on cholangiocarcinoma (called CARA). In MISEM, the response rate was 48.4%, a low but not unexpected rate as participation among population controls is usually lower and has been declining over time (5). It is important to underline that ReNaM applied the same questionnaire that was used for interviews and carried out the same exposure assessment as both MISEM and CARA. As repeatedly stated in ReNaM papers (6-7), each regional operating center assesses asbestos exposure based on the individual questionnaire, other available information, and knowledge of local industries. Occupational exposure to asbestos is classified as definite, probable or possible. Occupational exposure is (i) definite when the subject`s work was reported or otherwise known to have involved the use of asbestos or asbestos-containing materials (MCA); (ii) probable when subjects worked in factories where asbestos or MCA were used, but their personal exposure could not be documented; and (iii) possible when they were employed in industrial activities known to entail the use of asbestos or MCA. Hence, the definite and probable categories are closer to one another and were combined in our analyses. In any case, restricting analyses to subjects with definite occupational exposure and using each set of controls separately, as suggested by Mezei et al, yielded elevated OR for TVT and pericardial mesothelioma among men using both the above described modelling strategies; the OR could not be calculated for women. There were 70 (25 pericardial and 45 TVT) occupationally exposed mesothelioma cases. In population-based studies, analyses by occupation are limited by the low prevalence of most specific jobs. As briefly reported in our paper, for purely descriptive purposes, the industrial activity of exposure (cases may have multiple exposures), were construction (22 exposures, 7 and 15 for pericardial and TVT mesotheliomas, respectively), steel mills and other metal working industries (4 and 11), textile industries (2 and 3), and agriculture (2 and 5); other sectors had lower exposure frequencies. The absence of industries like asbestos-cement production, shipbuilding and railway carriages production/repair should not be surprising and had already been observed (7). In the Italian multicenter cohort study of asbestos workers (8), given the person-years of observation accrued by workers employed in these industries and gender- and site-specific crude incidence rates, approximately 0.1 case of pericardial and 0.2 of TVT mesothelioma would have been expected from 1970 to 2010. Even increasing ten-fold such figures to account for higher occupational risks among these workers would not change much. Asbestos exposure in agriculture has been repeatedly discussed in ReNaM reports (9: pages 70, 73, 128, 164 and 205). Exposure opportunities included the presence of asbestos in wine production, reuse of hessian bags previously containing asbestos, or construction and maintenance of rural buildings. Similarly, mesothelioma cases and agricultural workers exposed to asbestos have been noted in France (10). In conclusion, the additional analyses we performed according to Mezei et al's suggestions confirm the association between asbestos exposure and pericardial and TVT mesothelioma, supporting the causal role of asbestos for all mesotheliomas. ReNaM`s continuing surveillance system with national coverage is a precious platform for launching analytical studies on pleural and extra pleural mesothelioma. References 1. Mezei G, Chang ET, Mowat FS, Moolgavkar SH. Comments on a recent case-control study of malignant mesothelioma of the pericardium and the tunica vaginalis testis Scand J Work Environ Health. 2021;47(1):85-86. https://doi.org/10.5271/3909 2. Marinaccio A, Consonni D, Mensi C, Mirabelli D, Migliore E, Magnani C et al.; ReNaM Working Group. Association between asbestos exposure and pericardial and tunica vaginalis testis malignant mesothelioma: a case-control study and epidemiological remarks. Scand J Work Environ Health. 2020;46(6):609-617. https://doi.org/10.5271/sjweh.3895. 3. Greenland S. Control-initiated case-control studies. Int J Epidemiol 1985 Mar;14(1):130-4. https://doi.org/10.1093/ije/14.1.130. 4. Pearce N. Analysis of matched case-control studies. BMJ 2016 Feb;352:i969. https://doi.org/10.1136/bmj.i969. 5. Bigert C, Gustavsson P, Straif K, Pesch B, Brüning T, Kendzia B et al. Lung cancer risk among cooks when accounting for tobacco smoking: a pooled analysis of case-control studies from Europe, Canada, New Zealand, and China. J Occup Environ Med 2015 Feb;57(2):202-9. https://doi.org/10.1097/JOM.0000000000000337. 6. Marinaccio A, Binazzi A, Marzio DD, Scarselli A, Verardo M, Mirabelli D et al.; ReNaM Working Group. Pleural malignant mesothelioma epidemic: incidence, modalities of asbestos exposure and occupations involved from the Italian National Register. Int J Cancer 2012 May;130(9):2146-54. https://doi.org/10.1002/ijc.26229. 7. Marinaccio A, Binazzi A, Di Marzio D, Scarselli A, Verardo M, Mirabelli D et al. Incidence of extrapleural malignant mesothelioma and asbestos exposure, from the Italian national register. Occup Environ Med 2010 Nov;67(11):760-5. https://doi.org/10.1136/oem.2009.051466. 8. Ferrante D, Chellini E, Merler E, Pavone V, Silvestri S, Miligi L et al.; the working group. Italian pool of asbestos workers cohorts: mortality trends of asbestos-related neoplasms after long time since first exposure. Occup Environ Med 2017 Dec;74(12):887-98. https://doi.org/10.1136/oemed-2016-104100. 9. ReNaM VI Report. Available from: https://www.inail.it/cs/internet/docs/alg-pubbl-registro-nazionale-mesoteliomi-6-rapporto.pdf. Italian 10. Marant Micallef C, Shield KD, Vignat J, Baldi I, Charbotel B, Fervers B et al. Cancers in France in 2015 attributable to occupational exposures. Int J Hyg Environ Health 2019 Jan;222(1):22-9. https://doi.org/10.1016/j.ijheh.2018.07.015.
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http://dx.doi.org/10.5271/sjweh.3910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801133PMC
January 2021

Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 Mar 17;30(3):507-512. Epub 2020 Dec 17.

School of Public Health, Imperial College London, London, United Kingdom.

Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives.

Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure.

Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025.

Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population.

Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1438DOI Listing
March 2021

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

Clin Gastroenterol Hepatol 2020 Dec 29. Epub 2020 Dec 29.

Escuela Andaluza de Salud Pública, Granada, Spain.

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 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 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.
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http://dx.doi.org/10.1016/j.cgh.2020.11.045DOI Listing
December 2020

Plant foods, dietary fibre and risk of ischaemic heart disease in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Int J Epidemiol 2021 03;50(1):212-222

Department of Public Health and Clinical Medicine, Section of Sustainable Health/Nutritional Research, Umeå University, Umeå, Sweden.

Background: Epidemiological evidence indicates that diets rich in plant foods are associated with a lower risk of ischaemic heart disease (IHD), but there is sparse information on fruit and vegetable subtypes and sources of dietary fibre. This study examined the associations of major plant foods, their subtypes and dietary fibre with risk of IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: We conducted a prospective analysis of 490 311 men and women without a history of myocardial infarction or stroke at recruitment (12.6 years of follow-up, n cases = 8504), in 10 European countries. Dietary intake was assessed using validated questionnaires, calibrated with 24-h recalls. Multivariable Cox regressions were used to estimate hazard ratios (HR) of IHD.

Results: There was a lower risk of IHD with a higher intake of fruit and vegetables combined [HR per 200 g/day higher intake 0.94, 95% confidence interval (CI): 0.90-0.99, P-trend = 0.009], and with total fruits (per 100 g/day 0.97, 0.95-1.00, P-trend = 0.021). There was no evidence for a reduced risk for fruit subtypes, except for bananas. Risk was lower with higher intakes of nuts and seeds (per 10 g/day 0.90, 0.82-0.98, P-trend = 0.020), total fibre (per 10 g/day 0.91, 0.85-0.98, P-trend = 0.015), fruit and vegetable fibre (per 4 g/day 0.95, 0.91-0.99, P-trend = 0.022) and fruit fibre (per 2 g/day 0.97, 0.95-1.00, P-trend = 0.045). No associations were observed between vegetables, vegetables subtypes, legumes, cereals and IHD risk.

Conclusions: In this large prospective study, we found some small inverse associations between plant foods and IHD risk, with fruit and vegetables combined being the most strongly inversely associated with risk. Whether these small associations are causal remains unclear.
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http://dx.doi.org/10.1093/ije/dyaa155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938513PMC
March 2021

The impact of lifecourse socio-economic position and individual social mobility on breast cancer risk.

BMC Cancer 2020 Nov 23;20(1):1138. Epub 2020 Nov 23.

UMR LEASP, Université de Toulouse III, UPS, Inserm, Toulouse, France.

Background: Women with an advantaged socioeconomic position (SEP) have a higher risk of developing breast cancer (BC). The reasons for this association do not seem to be limited to reproductive factors and remain to be understood. We aimed to investigate the impact of lifecourse SEP from childhood and social mobility on the risk of BC considering a broad set of potential mediators.

Methods: We used a discovery-replication strategy in two European prospective cohorts, E3N (N = 83,436) and EPIC-Italy (N = 20,530). In E3N, 7877 women were diagnosed with BC during a median 24.4 years of follow-up, while in EPIC-Italy, 893 BC cases were diagnosed within 15.1 years. Hazard ratios (HR) were estimated using Cox proportional hazard models on imputed data.

Results: In E3N, women with higher education had a higher risk of BC (HR [95%CI] = 1.21 [1.12, 1.30]). This association was attenuated by adjusting for reproductive factors, in particular age at first childbirth (HR[95%CI] = 1.13 [1.04, 1.22]). Health behaviours, anthropometric variables, and BC screening had a weaker effect on the association. Women who remained in a stable advantaged SEP had a higher risk of BC (HR [95%CI] = 1.24 [1.07; 1.43]) attenuated after adjustment for potential mediators (HR [95%CI] = 1.13 [0.98; 1.31]). These results were replicated in EPIC-Italy.

Conclusions: These results confirm the important role of reproductive factors in the social gradient in BC risk, which does not appear to be fully explained by the large set of potential mediators, including cancer screening, suggesting that further research is needed to identify additional mechanisms.
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http://dx.doi.org/10.1186/s12885-020-07648-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684912PMC
November 2020

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.

Diabetes Care 2021 Jan 17;44(1):98-106. Epub 2020 Nov 17.

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory; Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet of Llobregat, Barcelona, Spain.

Objective: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.

Research Design And Methods: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.

Results: We identified 11 genomic regions associated with plasma vitamin C ( < 5 × 10), with the strongest signal at , and 10 novel genetic loci including , , , , , , , , , and . Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).

Conclusions: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
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http://dx.doi.org/10.2337/dc20-1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783939PMC
January 2021

Genome-wide association analysis of type 2 diabetes in the EPIC-InterAct study.

Sci Data 2020 11 13;7(1):393. Epub 2020 Nov 13.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.
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http://dx.doi.org/10.1038/s41597-020-00716-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666191PMC
November 2020

Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers.

Cancer Epidemiol Biomarkers Prev 2021 01 3;30(1):217-228. Epub 2020 Nov 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers.

Methods: Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data.

Results: Genetic correlation analysis revealed significant genetic correlation between the two cancers ( = 0.43, = 2.66 × 10). We found seven loci associated with risk for both cancers ( < 2.4 × 10). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified ( < 5 × 10). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation.

Conclusions: Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis.

Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0739DOI Listing
January 2021
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