Publications by authors named "Piet A van den Brandt"

332 Publications

Validity and Reproducibility of Immunohistochemical Scoring by Trained Non-Pathologists on Tissue Microarrays.

Cancer Epidemiol Biomarkers Prev 2021 Jul 16. Epub 2021 Jul 16.

Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, the Netherlands.

Background: Scoring of immunohistochemistry (IHC) staining is often done by non-pathologists, especially in large-scale tissue microarray (TMA)-based studies. Studies on the validity and reproducibility of scoring results from non-pathologists are limited. Therefore, our main aim was to assess interobserver agreement between trained non-pathologists and an experienced histopathologist for three IHC markers with different subcellular localization (nucleus/membrane/cytoplasm).

Methods: Three non-pathologists were trained in recognizing adenocarcinoma and IHC scoring by a senior histopathologist. Kappa statistics were used to analyze interobserver and intraobserver agreement for 6,249 TMA cores from a colorectal cancer series.

Results: Interobserver agreement between non-pathologists (independently scored) and the histopathologist was "substantial" for nuclear and membranous IHC markers (κ = 0.67-0.75 and κ = 0.61-0.69, respectively), and "moderate" for the cytoplasmic IHC marker (κ = 0.43-0.57). Scores of the three non-pathologists were also combined into a "combination score (if at least two non-pathologists independently assigned the same score to a core, this was the combination score). This increased agreement with the pathologist (κ = 0.74; κ = 0.73; κ = 0.57). Interobserver agreement between non-pathologists was "substantial" (κ = 0.78; κ = 0.72; κ = 0.61). Intraobserver agreement of non-pathologists was "substantial" to "almost perfect" (κ = 0.83-0.87; κ = 0.75-0.82; κ = 0.69). Overall, agreement was lowest for the cytoplasmic IHC marker.

Conclusions: This study shows that adequately trained non-pathologists are able to generate reproducible IHC scoring results, that are similar to those of an experienced histopathologist. A combination score of at least two non-pathologists yielded optimal results.

Impact: Non-pathologists can generate reproducible IHC results after appropriate training, making analyses of large-scale molecular pathological epidemiology studies feasible within an acceptable time frame.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0295DOI Listing
July 2021

Family history of cancer in first degree relatives and risk of cancer of unknown primary.

Eur J Cancer Care (Engl) 2021 Jul 5. Epub 2021 Jul 5.

Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands.

Objective: Cancer of Unknown Primary (CUP) refers to the presence of metastatic lesions, with no identifiable primary site during the patient's lifetime. Poor survival and lack of available treatment highlight the need to identify potential CUP risk factors. We investigated whether a family history of cancer is associated with increased CUP risk.

Methods: We performed a case cohort analysis using data from the Netherlands Cohort Study, which included a total of 963 CUP cases and 4,288 subcohort members. A Cox Proportional Hazards Regression was used to compare CUP risk in participants who reported to have a family member with cancer to those who did not, whilst adjusting for confounders.

Results: In general, we observed no increased CUP risk in those who reported a family history of cancer. CUP risk appeared slightly increased in those who reported cancer in a sibling (HR: 1.16, 95% CI: 0.97-1.38), especially in those with a sister with cancer compared with those without (HR: 1.23, 95% CI: 0.99-1.53), although these findings are not statistically significant.

Conclusion: Having a family history of cancer is not an independent risk factor of CUP.
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http://dx.doi.org/10.1111/ecc.13485DOI Listing
July 2021

Meat consumption and cancer of unknown primary (CUP) risk: results from The Netherlands cohort study on diet and cancer.

Eur J Nutr 2021 Jun 21. Epub 2021 Jun 21.

Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, PO Box 616, 6200, Maastricht, The Netherlands.

Purpose: Cancer of unknown primary (CUP) is a metastasised cancer for which no primary lesion could be identified during life. Research into CUP aetiology with respect to dietary factors is particularly scarce. This study investigates whether meat consumption is associated with CUP risk.

Methods: Data was utilised from the prospective Netherlands cohort study that includes 1,20,852 participants aged 55-69 years. All participants completed a self-administered questionnaire on diet and other cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. A total of 899 CUP cases and 4111 subcohort members with complete and consistent dietary data were available for case-cohort analyses after 20.3 years of follow-up. Multivariable adjusted hazard ratios (HRs) were calculated using proportional hazards models.

Results: We found a statistically significant positive association with beef and processed meat consumption and CUP risk in women (multivariable adjusted HR Q4 vs. Q1 1.47, 95% CI 1.04-2.07, P = 0.004 and Q4 vs. Q1 1.53, 95% CI 1.08-2.16, P = 0.001, respectively), and a non-significant positive association with processed meat consumption and CUP risk in men (multivariable adjusted HR Q4 vs. Q1 1.33, 95% CI 0.99-1.79, P = 0.15). No associations were observed between red meat (overall), poultry or fish consumption and CUP risk.

Conclusion: In this cohort, beef and processed meat consumption were positively associated with increased CUP risk in women, whereas a non-significant positive association was observed between processed meat consumption and CUP risk in men.
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http://dx.doi.org/10.1007/s00394-021-02600-5DOI Listing
June 2021

Dairy foods, calcium, and risk of breast cancer overall and for subtypes defined by estrogen receptor status: a pooled analysis of 21 cohort studies.

Am J Clin Nutr 2021 08;114(2):450-461

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.

Background: Epidemiologic studies examining the relations between dairy product and calcium intakes and breast cancer have been inconclusive, especially for tumor subtypes.

Objective: To evaluate the associations between intakes of specific dairy products and calcium and risk of breast cancer overall and for subtypes defined by estrogen receptor (ER) status.

Method: We pooled the individual-level data of over 1 million women who were followed for a maximum of 8-20 years across studies. Associations were evaluated for dairy product and calcium intakes and risk of incident invasive breast cancer overall (n = 37,861 cases) and by subtypes defined by ER status. Study-specific multivariable hazard ratios (HRs) were estimated and then combined using random-effects models.

Results: Overall, no clear association was observed between the consumption of specific dairy foods, dietary (from foods only) calcium, and total (from foods and supplements) calcium, and risk of overall breast cancer. Although each dairy product showed a null or very weak inverse association with risk of overall breast cancer (P, test for trend >0.05 for all), differences by ER status were suggested for yogurt and cottage/ricotta cheese with associations observed for ER-negative tumors only (pooled HR = 0.90, 95% CI: 0.83, 0.98 comparing ≥60 g/d with <1 g/d of yogurt and 0.85, 95% CI: 0.76, 0.95 comparing ≥25 g/d with <1 g/d of cottage/ricotta cheese). Dietary calcium intake was only weakly associated with breast cancer risk (pooled HR = 0.98, 95% CI: 0.97, 0.99 per 350 mg/d).

Conclusion: Our study shows that adult dairy or calcium consumption is unlikely to associate with a higher risk of breast cancer and that higher yogurt and cottage/ricotta cheese intakes were inversely associated with the risk of ER-negative breast cancer, a less hormonally dependent subtype with poor prognosis. Future studies on fermented dairy products, earlier life exposures, ER-negative breast cancer, and different racial/ethnic populations may further elucidate the relation.
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http://dx.doi.org/10.1093/ajcn/nqab097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326053PMC
August 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

Pan-cancer image-based detection of clinically actionable genetic alterations.

Nat Cancer 2020 Aug 27;1(8):789-799. Epub 2020 Jul 27.

Division of Gastroenterology, Hepatology and Gastrointestinal On-cology, University Hospital RWTH Aachen, Aachen, Germany.

Molecular alterations in cancer can cause phenotypic changes in tumor cells and their micro-environment. Routine histopathology tissue slides - which are ubiquitously available - can reflect such morphological changes. Here, we show that deep learning can consistently infer a wide range of genetic mutations, molecular tumor subtypes, gene expression signatures and standard pathology biomarkers directly from routine histology. We developed, optimized, validated and publicly released a one-stop-shop workflow and applied it to tissue slides of more than 5000 patients across multiple solid tumors. Our findings show that a single deep learning algorithm can be trained to predict a wide range of molecular alterations from routine, paraffin-embedded histology slides stained with hematoxylin and eosin. These predictions generalize to other populations and are spatially resolved. Our method can be implemented on mobile hardware, potentially enabling point-of-care diagnostics for personalized cancer treatment. More generally, this approach could elucidate and quantify genotype-phenotype links in cancer.
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http://dx.doi.org/10.1038/s43018-020-0087-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610412PMC
August 2020

The Role of Novel (Tobacco) Products on Tobacco Control in Italy.

Int J Environ Res Public Health 2021 02 16;18(4). Epub 2021 Feb 16.

Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy.

In Italy, electronic cigarettes have spread since 2010 and heated tobacco products (HTP) since 2016. We investigated their public health consequences on conventional cigarette smoking, taking advantage of a series of cross-sectional studies annually conducted between 2001 and 2019 in Italy. Every year, the sample, including around 3000 individuals, was representative of the general Italian population aged ≥15 years. In Italy, smoking prevalence steadily declined from 29.1% in 2001 to 20.6% in 2013, then increased to 22.0% in 2019. In 2017-2019, current electronic cigarette users were 2.1% and in 2019 current HTP users were 1.1%. Among 498 ever electronic cigarette users, 23.2% started or re-started smoking and 15.7% quit smoking after electronic cigarette use; of 49 ever HTP users, 19.1% started or re-started smoking combusted cigarettes and 14.6% quit smoking after HTP use. The availability of novel products in Italy resulted in a halt of the decreasing trend in smoking prevalence. For the first time, we observed an increase of Italians inhaling nicotine, concurrently with the spread of novel (tobacco) products. More importantly, the use of novel products appears to increase-rather than decrease-the likelihood of smoking conventional cigarettes. Considering this evidence, we see no argument to justify the huge fiscal and regulatory benefits these products continue to have, at least in Italy.
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http://dx.doi.org/10.3390/ijerph18041895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920305PMC
February 2021

Deep learning detects genetic alterations in cancer histology generated by adversarial networks.

J Pathol 2021 May 16;254(1):70-79. Epub 2021 Mar 16.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Deep learning can detect microsatellite instability (MSI) from routine histology images in colorectal cancer (CRC). However, ethical and legal barriers impede sharing of images and genetic data, hampering development of new algorithms for detection of MSI and other biomarkers. We hypothesized that histology images synthesized by conditional generative adversarial networks (CGANs) retain information about genetic alterations. To test this, we developed a 'histology CGAN' which was trained on 256 patients (training cohort 1) and 1457 patients (training cohort 2). The CGAN synthesized 10 000 synthetic MSI and non-MSI images which contained a range of tissue types and were deemed realistic by trained observers in a blinded study. Subsequently, we trained a deep learning detector of MSI on real or synthetic images and evaluated the performance of MSI detection in a held-out set of 142 patients. When trained on real images from training cohort 1, this system achieved an area under the receiver operating curve (AUROC) of 0.742 [0.681, 0.854]. Training on the larger cohort 2 only marginally improved the AUROC to 0.757 [0.707, 0.869]. Training on purely synthetic data resulted in an AUROC of 0.743 [0.658, 0.801]. Training on both real and synthetic data further increased AUROC to 0.777 [0.715, 0.821]. We conclude that synthetic histology images retain information reflecting underlying genetic alterations in colorectal cancer. Using synthetic instead of real images to train deep learning systems yields non-inferior classifiers. This approach can be used to create large shareable data sets or to augment small data sets with rare molecular features. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5638DOI Listing
May 2021

Parental lifespan and the likelihood of reaching the age of 90 years in the Netherlands Cohort Study.

Geriatr Gerontol Int 2021 Feb 26;21(2):215-221. Epub 2020 Dec 26.

GROW - School for Oncology and Developmental Biology, Department of Epidemiology, Maastricht University Medical Center, Maastricht, the Netherlands.

Aim: Growing evidence suggests an association between parental longevity and lifespan of subsequent generations. We aimed to reproduce earlier findings, showing a positive association between parental longevity and offspring's longevity. Additionally, we investigated whether this is mainly driven by the maternal or paternal germline in male and female offspring.

Methods: For these analyses, data from the oldest birth cohort (1916-17) of the Netherlands Cohort Study was used. Participants filled in a baseline questionnaire in 1986 (at age 68-70 years). Follow up for vital status information until the age of 90 years (2006-07) was >99.9% complete. Multivariable-adjusted Cox regression analyses with a fixed follow-up time were based on 2368 men and 2657 women with complete parental survival data and relevant confounders to calculate risk ratios (RR) of reaching longevity.

Results: In age-adjusted models, paternal and maternal age at death were significantly positively associated with reaching 90 years in both male and female offspring. In male offspring, paternal age at death (≥90 years vs <80 years) showed the strongest association with survival to 90 years (RR 1.42, 95% CI 1.07-1.89), after confounder correction. In female offspring, maternal age at death (≥90 years vs <80 years) showed the strongest association with survival to 90 years (RR 1.20, 95% CI 1.04-1.40).

Discussion: After confounder adjustment, stronger and significant associations were observed between paternal lifespan and male offspring longevity, and maternal lifespan and female offspring longevity. Future research should investigate through which pathways a longer lifespan of parents is transmitted to their offspring. Geriatr Gerontol Int 2021; 21: 215-221.
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http://dx.doi.org/10.1111/ggi.14120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898670PMC
February 2021

Body size and weight change over adulthood and risk of breast cancer by menopausal and hormone receptor status: a pooled analysis of 20 prospective cohort studies.

Eur J Epidemiol 2021 Jan 30;36(1):37-55. Epub 2020 Oct 30.

Epidemiology and Prevention Group, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m, respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.
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http://dx.doi.org/10.1007/s10654-020-00688-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847460PMC
January 2021

Pregnancy outcomes and risk of endometrial cancer: A pooled analysis of individual participant data in the Epidemiology of Endometrial Cancer Consortium.

Int J Cancer 2021 05 17;148(9):2068-2078. Epub 2020 Nov 17.

Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further ~15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
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http://dx.doi.org/10.1002/ijc.33360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969437PMC
May 2021

Anthropometry, physical activity and cancer of unknown primary (CUP) risk: Results from the Netherlands cohort study.

Cancer Epidemiol 2020 12 21;69:101836. Epub 2020 Oct 21.

Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, The Netherlands.

Background: Cancer of Unknown Primary (CUP) is a metastatic disease for which the primary tumour origin could not be identified during life. Few studies have investigated the risk factors associated with this disease. This study investigates anthropometry, physical activity and CUP risk.

Methods: Data is used from the Netherlands Cohort Study, which includes 120,852 participants aged 55-69 years. All cohort members completed a self-administered questionnaire on cancer risk factors at baseline in 1986. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and the Dutch Pathology Registry. After a follow-up of 20.3 years, 926 incident CUP cases and 4099 subcohort members were available for case-cohort analyses. Proportional hazards models were used to compute multivariable adjusted hazard ratios (HRs).

Results: We found no associations between height, body mass index (BMI) at baseline, BMI at age 20 years, change in BMI since age 20 years, clothing size (trouser/skirt size), or non-occupational physical activity and CUP risk.

Conclusion: Our findings indicate that neither anthropometry nor physical activity are associated with the development of CUP.
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http://dx.doi.org/10.1016/j.canep.2020.101836DOI Listing
December 2020

Alcohol consumption, cigarette smoking and cancer of unknown primary risk: Results from the Netherlands Cohort Study.

Int J Cancer 2021 04 20;148(7):1586-1597. Epub 2020 Oct 20.

Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Cancer of unknown primary (CUP) is a metastasised malignancy with no identifiable primary tumour origin. Despite the frequent occurrence and bleak prognosis of CUP, research into its aetiology is scarce. Our study investigates alcohol consumption, tobacco smoking and CUP risk. We used data from the Netherlands Cohort Study, a cohort that includes 120 852 participants aged 55 to 69 years, who completed a self-administered questionnaire on cancer risk factors at baseline. Cancer follow-up was established through record linkage to the Netherlands Cancer Registry and Dutch Pathology Registry. After 20.3 years of follow-up, 963 CUP cases and 4288 subcohort members were available for case-cohort analyses. Multivariable-adjusted hazard ratios (HRs) were calculated using proportional hazard models. In general, CUP risk increased with higher levels of alcohol intake (P = .02). The association was more pronounced in participants who drank ≥30 g of ethanol per day (HR: 1.57, 95% confidence interval [CI]: 1.20-2.05) compared to abstainers. Current smokers were at an increased CUP risk (HR: 1.59, 95% CI: 1.29-1.97) compared to never smokers. We observed that the more the cigarettes or the longer a participant smoked, the higher the CUP risk was (P = .003 and P = .02, respectively). Interaction on additive scale was found for participants with the highest exposure categories of alcohol consumption and cigarette smoking frequency and CUP risk. Our findings demonstrate that alcohol consumption and cigarette smoking are associated with increased CUP risk. Lifestyle recommendations for cancer prevention regarding not drinking alcohol and avoiding exposure to smoking are therefore also valid for CUP.
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http://dx.doi.org/10.1002/ijc.33328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894525PMC
April 2021

Adherence to the Mediterranean Diet and Overall Cancer Incidence: The Netherlands Cohort Study.

J Acad Nutr Diet 2021 02 25;121(2):242-252. Epub 2020 Sep 25.

Background: Mediterranean diet adherence has been associated with reduced risks of various cancer types. However, prospective findings for overall cancer risk are inconclusive.

Objective: The aim of this study was to examine sex-specific relations of Mediterranean diet adherence with overall cancer risk.

Design: This analysis was conducted as part of the prospective Netherlands Cohort Study. Baseline data on diet and other cancer risk factors were collected using a self-administered questionnaire. Participants were followed up for cancer incidence for 20.3 years through record linkages with the Netherlands Cancer Registry and the Dutch Pathology Registry. The alternate Mediterranean diet score without alcohol was the principal measure of Mediterranean diet adherence.

Participants/setting: The study population consisted of 120,852 inhabitants of the Netherlands, who were aged 55 to 69 years in September 1986.

Main Outcome Measure: The primary outcome was overall cancer incidence.

Statistical Analyses Performed: Cox regression analyses (case-cohort design) were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of Mediterranean diet adherence with incidence of cancer (subgroups). In total, 12,184 male and 7,071 female subjects with cancer had complete data on potential confounders and were eligible for inclusion in the Cox models.

Results: Middle compared with low Mediterranean diet adherence (alternate Mediterranean diet score without alcohol) was significantly associated with a reduced overall cancer risk in women (HR [95% CI]: 0.85 [0.75-0.97]). Decreased HR estimates for the highest Mediterranean diet adherence category and per 2-point increase in score were also observed, but did not reach statistical significance in multivariable-adjusted analyses. In men, there was no evidence of an association for overall cancer risk (HR [95% CI]: 1.02 [0.95-1.10]). Results for cancer subgroups, defined by relations with tobacco smoking, obesity, and alcohol consumption, were largely similar to the overall findings. Model fits diminished when alcohol was included in the Mediterranean diet score.

Conclusions: Mediterranean diet adherence was not associated with overall cancer risk in male participants of the prospective Netherlands Cohort Study. HR estimates in women pointed in the inverse direction, but lost statistical significance after full adjustment for confounding in most cases.
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http://dx.doi.org/10.1016/j.jand.2020.07.025DOI Listing
February 2021

Loneliness in Later Life and Reaching Longevity: Findings From the Longitudinal Aging Study Amsterdam.

J Gerontol B Psychol Sci Soc Sci 2021 01;76(2):415-424

Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, the Netherlands.

Objectives: There is an increasing research interest in factors that characterize those who reach exceptionally old ages. Although loneliness is often associated with an increased risk for premature mortality, its relationship with reaching longevity is still unclear. We aimed to quantify the association between (social/emotional) loneliness and the likelihood of reaching the age of 90 years in men and women separately.

Methods: For these analyses, data from the Longitudinal Aging Study Amsterdam (LASA) were used. Loneliness, social loneliness, and emotional loneliness were assessed at baseline using the 11-item De Jong-Gierveld scale in 1992-1993 (at age 64-85 years). Follow-up for vital status information until the age of 90 years was 99.5% completed. Multivariable-adjusted Cox regression analyses with a fixed follow-up time were based on 1,032 men and 1,078 women to calculate risk ratios (RR) of reaching 90 years.

Results: No significant associations were observed between loneliness and reaching 90 years in both men (RR, 0.90; 95% confidence interval [CI], 0.70-1.14) and women (RR, 0.98; 95% CI, 0.83-1.14). Social loneliness was significantly associated with a reduced chance of reaching 90 years in women (RR, 0.82; 95% CI, 0.67-0.99).

Discussion: The current analyses did not show support for the existence of a meaningful effect of loneliness on reaching longevity in both sexes. When investigating specific dimensions of loneliness, we observed that reporting social loneliness was associated with reaching 90 years in women. This indicates that, for women, a large and diverse personal network at an older age could increase the probability of reaching longevity. However, replication of our findings in other cohorts is needed.
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http://dx.doi.org/10.1093/geronb/gbaa145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813181PMC
January 2021

Ovarian Cancer Risk Factor Associations by Primary Anatomic Site: The Ovarian Cancer Cohort Consortium.

Cancer Epidemiol Biomarkers Prev 2020 10 30;29(10):2010-2018. Epub 2020 Jul 30.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites.

Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests.

Results: Most associations did not vary by tumor site ( ≥ 0.05). Associations between first pregnancy ( = 0.04), tubal ligation ( = 0.01), and early-adult (age 18-21 years) body mass index (BMI; = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer ( = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases.

Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site.

Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541500PMC
October 2020

Nut and Peanut Butter Consumption and the Risk of Total Cancer: A Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2020 10 29;29(10):2100-2104. Epub 2020 Jul 29.

Maastricht University Medical Center+, Care and Public Health Research Institute (CAPHRI), Department of Epidemiology, Maastricht, Limburg, the Netherlands.

Background: Nut intake has been associated with reduced cancer-related mortality, but there is very limited evidence on total cancer risk. We investigated the associations of nut and peanut butter intake with the risk of total cancer and smoking- and alcohol-related cancer subgroups.

Methods: In the prospective Netherlands Cohort Study, 120,852 men and women aged 55 to 69 years provided information on lifestyle and dietary habits at baseline in 1986. After 20.3 years of follow-up, 19,255 total cancer cases and 3,499 subcohort members were included in multivariable-adjusted Cox regression analyses, using a case-cohort approach.

Results: No significant associations were found between total nut, tree nut, peanut, and peanut butter intake and total cancer risk in men and women. There were also no significant associations with smoking-(un)related and alcohol-(un)related cancers in both sexes.

Conclusions: Our findings suggest that nut and peanut butter intake are not associated with a reduced risk of total cancer in men or women.

Impact: Nut and peanut butter consumption are not related to the risk of total cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0456DOI Listing
October 2020

Nut and peanut butter intake and the risk of colorectal cancer and its anatomical and molecular subtypes: the Netherlands Cohort Study.

Carcinogenesis 2020 10;41(10):1368-1384

Department of Epidemiology, Care and Public Health Research Institute (CAPHRI).

Nut intake has been associated with reduced total cancer-related mortality, but evidence for colorectal cancer (CRC) risk is inconclusive. We investigated the associations between nut and peanut butter intake and anatomical CRC subtypes. To account for molecular heterogeneity, associations between nut and peanut butter intake and colorectal tumors harboring APC, KRAS or BRAF mutations, p53 overexpression or microsatellite instability were examined in secondary analyses. In the Netherlands Cohort Study (n = 120 852), lifestyle habits were measured with a questionnaire in 1986. After 20.3 years follow-up, 3567 CRC cases were included in case-cohort analyses. For the analyses of molecular CRC subtypes, 574 cases were included after 7.3 years follow-up. In categorical analyses, total nut intake was not significantly associated with CRC [HR (95% CI) 10+ g/day versus non-consumers = 0.94(0.78-1.15) in men; 0.96(0.75-1.22) in women]. In restricted cubic spline analyses, significant non-linear inverse associations with rectal cancer were observed for total nut, peanut and peanut butter intake in women, and borderline significant non-linear inverse associations for total nut and peanut intake in men. Regarding the molecular CRC subtypes, peanut butter intake was significantly associated with an increased risk of colorectal tumors that did not develop through the serrated neoplasia pathway in men [HR (95% CI) per 5 g/day increment = 1.22(1.07-1.38)]. Nut and peanut butter intake are non-linearly inversely associated with rectal cancer risk in women. In men, nut intake is borderline significantly non-linearly associated with a reduced rectal cancer risk. Peanut butter is associated with an increased risk of colorectal tumors that do not develop through the serrated neoplasia pathway in men.
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http://dx.doi.org/10.1093/carcin/bgaa080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566329PMC
October 2020

Etiologic heterogeneity of clear-cell and papillary renal cell carcinoma in the Netherlands Cohort Study.

Int J Cancer 2021 01 13;148(1):67-76. Epub 2020 Jul 13.

Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

At present, mostly case-control and retrospective studies have investigated the association between etiologic risk factors and the development of histologic subtypes of renal cell carcinoma (RCC). Therefore, we assessed the heterogeneity between body mass index (BMI), cigarette smoking, alcohol consumption and hypertension across clear-cell RCC (ccRCC) and papillary RCC (pRCC) risk in the prospective Netherlands Cohort Study on diet and cancer. In 1986, 120 852 participants aged 55 to 69 completed a self-administered questionnaire on diet and other risk factors for cancer. Participants were followed up for cancer through record linkage. Tumor histology was assessed through centralized revision by two experienced uropathologists. After 20.3 years of follow-up, 384 histologically verified RCC cases, including 315 ccRCC and 46 pRCC cases and 4144 subcohort members were eligible for case-cohort analysis. Hazard ratios and 95% confidence intervals were estimated by multivariable-adjusted proportional hazards models. Overall, BMI was associated positively with ccRCC risk, but inversely with pRCC risk. Cigarette smoking was associated with an increased ccRCC, but a decreased pRCC risk. Alcohol consumption was inversely associated with both ccRCC and pRCC risk. Hypertension was associated with an increased risk of both ccRCC and pRCC. Statistically significant etiologic heterogeneity was observed for BMI, BMI change since age 20, and smoking duration in current smokers across ccRCC and pRCC risk. In conclusion, we observed potential heterogeneity for BMI, BMI change and smoking duration across ccRCC and pRCC risk.
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http://dx.doi.org/10.1002/ijc.33193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689694PMC
January 2021

Clinical-Grade Detection of Microsatellite Instability in Colorectal Tumors by Deep Learning.

Gastroenterology 2020 10 17;159(4):1406-1416.e11. Epub 2020 Jun 17.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, United Kingdom; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany; Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Background & Aims: Microsatellite instability (MSI) and mismatch-repair deficiency (dMMR) in colorectal tumors are used to select treatment for patients. Deep learning can detect MSI and dMMR in tumor samples on routine histology slides faster and less expensively than molecular assays. However, clinical application of this technology requires high performance and multisite validation, which have not yet been performed.

Methods: We collected H&E-stained slides and findings from molecular analyses for MSI and dMMR from 8836 colorectal tumors (of all stages) included in the MSIDETECT consortium study, from Germany, the Netherlands, the United Kingdom, and the United States. Specimens with dMMR were identified by immunohistochemistry analyses of tissue microarrays for loss of MLH1, MSH2, MSH6, and/or PMS2. Specimens with MSI were identified by genetic analyses. We trained a deep-learning detector to identify samples with MSI from these slides; performance was assessed by cross-validation (N = 6406 specimens) and validated in an external cohort (n = 771 specimens). Prespecified endpoints were area under the receiver operating characteristic (AUROC) curve and area under the precision-recall curve (AUPRC).

Results: The deep-learning detector identified specimens with dMMR or MSI with a mean AUROC curve of 0.92 (lower bound, 0.91; upper bound, 0.93) and an AUPRC of 0.63 (range, 0.59-0.65), or 67% specificity and 95% sensitivity, in the cross-validation development cohort. In the validation cohort, the classifier identified samples with dMMR with an AUROC of 0.95 (range, 0.92-0.96) without image preprocessing and an AUROC of 0.96 (range, 0.93-0.98) after color normalization.

Conclusions: We developed a deep-learning system that detects colorectal cancer specimens with dMMR or MSI using H&E-stained slides; it detected tissues with dMMR with an AUROC of 0.96 in a large, international validation cohort. This system might be used for high-throughput, low-cost evaluation of colorectal tissue specimens.
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http://dx.doi.org/10.1053/j.gastro.2020.06.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578071PMC
October 2020

Fruit consumption and the risk of bladder cancer: A pooled analysis by the Bladder Cancer Epidemiology and Nutritional Determinants Study.

Int J Cancer 2020 10 28;147(8):2091-2100. Epub 2020 Apr 28.

Department of Complex Genetics and Epidemiology, School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands.

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.
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http://dx.doi.org/10.1002/ijc.33008DOI Listing
October 2020

Exposure to secondhand aerosol of electronic cigarettes in indoor settings in 12 European countries: data from the TackSHS survey.

Tob Control 2021 01 2;30(1):49-56. Epub 2020 Mar 2.

Department of Environmental Health Sciences, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.

Introduction: Exposure to secondhand aerosol from e-cigarette (SHA) may pose harmful effects to bystanders. This study aims to investigate the prevalence, duration and determinants of SHA exposure in various indoor settings in 12 European countries.

Methods: In 2017-2018, we conducted a cross-sectional study, the TackSHS survey, on a representative sample of the population aged ≥15 years in 12 European countries (Bulgaria, England, France, Germany, Greece, Ireland, Italy, Latvia, Poland, Portugal, Romania and Spain). We described the prevalence and duration of exposure to SHA in several indoor settings among 11 604 e-cigarette non-users. Individual-level and country-level characteristics associated with SHA exposure were also explored using multilevel logistic regression analyses.

Results: Overall, 16.0% of e-cigarette non-users were exposed to SHA in any indoor setting at least weekly, ranging from 4.3% in Spain to 29.6% in England. The median duration of SHA exposure among those who were exposed was 43 min/day. 'Other indoor settings' (eg, bar and restaurant) was reported as the place where most of e-cigarette non-users were exposed (8.3%), followed by workplace/educational venues (6.4%), home (5.8%), public transportation (3.5%) and private transportation (2.7%). SHA exposure was more likely to occur in certain groups of non-users: men, younger age groups, those with higher level of education, e-cigarette past users, current smokers, those perceiving SHA harmless and living in countries with a higher e-cigarette use prevalence.

Conclusions: We found inequalities of SHA exposure across and within European countries. Governments should consider extending their tobacco smoke-free legislation to e-cigarettes to protect bystanders, particularly vulnerable populations such as young people.

Trial Registration Number: NCT02928536.
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http://dx.doi.org/10.1136/tobaccocontrol-2019-055376DOI Listing
January 2021

Alcohol consumption in later life and reaching longevity: the Netherlands Cohort Study.

Age Ageing 2020 04;49(3):395-402

Department of Epidemiology, Maastricht University Medical Centre, GROW- School for Oncology and Developmental Biology, Maastricht, The Netherlands.

Background: whether light-to-moderate alcohol intake is related to reduced mortality remains a subject of intense research and controversy. There are very few studies available on alcohol and reaching longevity.

Methods: we investigated the relationship of alcohol drinking characteristics with the probability to reach 90 years of age. Analyses were conducted using data from the Netherlands Cohort Study. Participants born in 1916-1917 (n = 7,807) completed a questionnaire in 1986 (age 68-70 years) and were followed up for vital status until the age of 90 years (2006-07). Multivariable Cox regression analyses with fixed follow-up time were based on 5,479 participants with complete data to calculate risk ratios (RRs) of reaching longevity (age 90 years).

Results: we found statistically significant positive associations between baseline alcohol intake and the probability of reaching 90 years in both men and women. Overall, the highest probability of reaching 90 was found in those consuming 5- < 15 g/d alcohol, with RR = 1.36 (95% CI, 1.20-1.55) when compared with abstainers. The exposure-response relationship was significantly non-linear in women, but not in men. Wine intake was positively associated with longevity (notably in women), whereas liquor was positively associated with longevity in men and inversely in women. Binge drinking pointed towards an inverse relationship with longevity. Alcohol intake was associated with longevity in those without and with a history of selected diseases.

Conclusions: the highest probability of reaching 90 years was found for those drinking 5- < 15 g alcohol/day. Although not significant, the risk estimates also indicate to avoid binge drinking.
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http://dx.doi.org/10.1093/ageing/afaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187870PMC
April 2020

The Risk of Ovarian Cancer Increases with an Increase in the Lifetime Number of Ovulatory Cycles: An Analysis from the Ovarian Cancer Cohort Consortium (OC3).

Cancer Res 2020 03 13;80(5):1210-1218. Epub 2020 Jan 13.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.

Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056529PMC
March 2020

Nutrient-wide association study of 92 foods and nutrients and breast cancer risk.

Breast Cancer Res 2020 01 13;22(1). Epub 2020 Jan 13.

Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

Background: Several dietary factors have been reported to be associated with risk of breast cancer, but to date, unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study.

Methods: Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS).

Results: Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% CI 1.03-1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03-1.06 and 1.04, 95% CI 1.02-1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94-0.98; 0.96, 95% CI 0.94-0.99; and 0.96, 95% CI 0.95-0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS.

Conclusions: Our findings confirm a positive association of alcohol consumption and suggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.
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http://dx.doi.org/10.1186/s13058-019-1244-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958698PMC
January 2020

Germline polymorphisms in the Von Hippel-Lindau and Hypoxia-inducible factor 1-alpha genes, gene-environment and gene-gene interactions and renal cell cancer.

Sci Rep 2020 01 10;10(1):137. Epub 2020 Jan 10.

Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.

We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in Von Hippel-Lindau (VHL) and Hypoxia-inducible factor 1-alpha (HIF1A), and their gene-environment and gene-gene interactions, and clear-cell RCC (ccRCC) risk. Furthermore, we assessed the relationship between VHL SNPs and VHL promoter methylation. Three VHL polymorphisms and one HIF1A polymorphism were genotyped in the Netherlands Cohort Study. In 1986, 120,852 participants aged 55-69 completed a self-administered questionnaire on diet and lifestyle and toenail clippings were collected. Toenail DNA was genotyped using the Sequenom MassARRAY platform. After 20.3 years, 3004 subcohort members and 406 RCC cases, of which 263 ccRCC cases, were eligible for multivariate case-cohort analyses. VHL_rs779805 was associated with RCC (Hazard Ratio (HR) 1.53; 95% Confidence Interval (CI) 1.07-2.17) and ccRCC risk (HR 1.88; 95% CI 1.25-2.81). No associations were found for other SNPs. Potential gene-environment interactions were found between alcohol consumption and selected SNPs. However, none remained statistically significant after multiple comparison correction. No gene-gene interactions were observed between VHL and HIF1A. VHL promoter methylation was not associated with VHL SNPs. VHL SNPs may increase (cc)RCC susceptibility. No associations were found between gene-environment and gene-gene interactions and (cc)RCC risk and between VHL promoter methylation and VHL SNPs.
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http://dx.doi.org/10.1038/s41598-019-56980-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954183PMC
January 2020

Reproductive and Hormonal Factors and Risk of Ovarian Cancer by Tumor Dominance: Results from the Ovarian Cancer Cohort Consortium (OC3).

Cancer Epidemiol Biomarkers Prev 2020 01 12;29(1):200-207. Epub 2019 Nov 12.

Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Background: Laterality of epithelial ovarian tumors may reflect the underlying carcinogenic pathways and origins of tumor cells.

Methods: We pooled data from 9 prospective studies participating in the Ovarian Cancer Cohort Consortium. Information on measures of tumor size or tumor dominance was extracted from surgical pathology reports or obtained through cancer registries. We defined dominant tumors as those restricted to one ovary or where the dimension of one ovary was at least twice as large as the other, and nondominant tumors as those with similar dimensions across the two ovaries or peritoneal tumors. Competing risks Cox models were used to examine whether associations with reproductive and hormonal risk factors differed by ovarian tumor dominance.

Results: Of 1,058 ovarian cancer cases with tumor dominance information, 401 were left-dominant, 363 were right-dominant, and 294 were nondominant. Parity was more strongly inversely associated with risk of dominant than nondominant ovarian cancer ( = 0.004). Ever use of oral contraceptives (OC) was associated with lower risk of dominant tumors, but was not associated with nondominant tumors ( = 0.01). Higher body mass index was associated with higher risk of left-dominant tumors, but not significantly associated with risk of right-dominant or nondominant tumors ( = 0.08).

Conclusions: These data suggest that reproductive and hormonal risk factors appear to have a stronger impact on dominant tumors, which may have an ovarian or endometriosis origin.

Impact: Examining the associations of ovarian cancer risk factors by tumor dominance may help elucidate the mechanisms through which these factors influence ovarian cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954293PMC
January 2020

A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study.

Eur J Nutr 2020 Oct 8;59(7):2929-2937. Epub 2019 Nov 8.

Hellenic Health Foundation, Athens, Greece.

Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive.

Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS).

Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS.

Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.
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http://dx.doi.org/10.1007/s00394-019-02132-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501135PMC
October 2020

Nut and peanut butter intake are not directly associated with the risk of endometrial or ovarian cancer: Results from a Dutch prospective cohort study.

Clin Nutr 2020 07 26;39(7):2202-2210. Epub 2019 Sep 26.

Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center+, P.O. Box 616, 6200 MD, Maastricht, the Netherlands; Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center+, P.O. Box 616, 6200 MD, Maastricht, the Netherlands. Electronic address:

Background & Aims: Nut intake has been associated with reduced cancer-related mortality and cancer risk. However, very few studies investigated the association between nut consumption and the risk of endometrial and ovarian cancer, with inconclusive results. We prospectively examined the relation between total nut, tree nut, peanut, and peanut butter intake and the risk of endometrial and ovarian cancer in the prospective Netherlands Cohort Study (NLCS).

Methods: In 1986, 62,573 women aged 55-69 years were included in the NLCS. At baseline, all participants filled in a questionnaire and a subcohort of 2589 women was randomly selected. After 20.3 years of follow-up, 389 endometrial and 347 ovarian cancer cases with complete data were included in the analysis. Hazard ratios (HRs) were calculated in multivariable-adjusted Cox regression analyses, using a case-cohort approach.

Results: Compared to nonconsumers, the HRs (95% confidence intervals) for women consuming 10 + g total nuts/day were 1.23 (0.82-1.87) for endometrial cancer and 0.84 (0.57-1.24) for ovarian cancer. For tree nut, peanut, and peanut butter intake, also no significant relations with endometrial or ovarian cancer were observed. In the endometrial cancer analyses, significant interactions of total nut intake with body mass index and cigarette smoking status were found.

Conclusions: The results of this study suggest that intake of total nuts, tree nuts, peanuts, and peanut butter is not related to the risk of endometrial or ovarian cancer. The observed interactions in the endometrial cancer analyses, in particular with cigarette smoking status, require confirmation in other studies.
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http://dx.doi.org/10.1016/j.clnu.2019.09.008DOI Listing
July 2020

Mediterranean diet adherence and risk of colorectal cancer: the prospective Netherlands Cohort Study.

Eur J Epidemiol 2020 Jan 7;35(1):25-35. Epub 2019 Sep 7.

Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

Mediterranean diet (MD) adherence has been associated with a large variety of health benefits. However, prospective studies investigating the relation between MD adherence and colorectal cancer risk had inconsistent results. In this analysis of the Netherlands Cohort Study (NLCS), we evaluated sex- and subsite-specific associations of MD adherence with colorectal cancer risk. In 1986, 120,852 subjects filled out the NLCS baseline questionnaire, which incorporated a 150-item food frequency questionnaire. MD adherence was estimated through alternate Mediterranean diet scores including and excluding alcohol (aMED and aMEDr, respectively). Using 20.3 year follow-up data, 1993 male and 1574 female colorectal cancer cases could be included in multivariable case-cohort analyses. aMEDr was not significantly associated with colorectal cancer risk, regardless of sex. Hazard ratios (95% confidence intervals) per two-point increment were 1.04 (0.95-1.13) for men and 0.97 (0.88-1.07) for women. Additionally, there was no evidence of an inverse association with any of the colorectal cancer subsites (colon, proximal colon, distal colon, and rectum). In women, the association between aMEDr and colorectal cancer risk was significantly modified by smoking status (P = 0.015). Comparable results were obtained for the original aMED including alcohol. In conclusion, higher MD adherence was not associated with a reduced risk of colorectal cancer or anatomical subsites in the context of a Dutch population.
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http://dx.doi.org/10.1007/s10654-019-00549-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058569PMC
January 2020
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