Nutrient-Wide Association Study of 92 Foods and Nutrients and Breast Cancer Risk

Alicia K. Heath; David C. Muller; Piet A. van den Brandt; Nikos Papadimitriou; Elena Critselis; Marc Gunter; Paolo Vineis; Elisabete Weiderpass; Guy Fagherazzi; Heiner Boeing; Pietro Ferrari; Anja Olsen; Anne Tjønneland; Patrick Arveux; Marie-Christine Boutron-Ruault; Francesca Romana Mancini; Tilman Kühn; Renée Turzanski-Fortner; Matthias B. Schulze; Anna Karakatsani; Paschalis Thriskos; Antonia Trichopoulou; Giovanna Masala; Paolo Contiero; Fulvio Ricceri; Salvatore Panico; Bas Bueno-de-Mesquita; Marije F. Bakker; Carla H. van Gils; Karina Standahl Olsen; Guri Skeie; Cristina Lasheras; Antonio Agudo; Miguel Rodríguez-Barranco; Maria-José Sánchez; Pilar Amiano; María-Dolores Chirlaque; Aurelio Barricarte; Isabel Drake; Ulrika Ericson; Ingegerd Johansson; Anna Winkvist; Tim Key; Heinz Freisling; Mathilde His; Inge Huybrechts; Sofia Christakoudi; Merete Ellingjord-Dale; Elio Riboli; Konstantinos K. Tsilidis; Ioanna Tzoulaki

Disclosures

Breast Cancer Res. 2020;22(5)

Conclusions

This study confirms the well-established increased risk of breast cancer associated with alcohol consumption and suggests that higher intake of dietary fibre and possibly fruit might be associated with reduced breast cancer risk.

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Abbreviations
BMI: Body Mass Index; CI: Confidence interval; EPIC: European Prospective Investigation into Cancer and Nutrition; ER: Oestrogen receptor; FDR: False discovery rate; GWAS: Genome-wide association study; HR: Hazard ratio; NLCS: Netherlands Cohort Study; NWAS: Nutrient-wide association study; PR: Progesterone receptor; RR: Relative risk; SD: Standard deviation; WCRF/AICR: World Cancer Research Fund/American Institute for Cancer Research

Acknowledgements
The authors thank all participants in the EPIC cohort for their invaluable contribution to the study.

Disclaimer
Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.

Funding
This work was supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (WCRF 2014/1180 to Konstantinos K Tsilidis).
The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia, Navarra, and the Catalan Institute of Oncology (Barcelona) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK).
The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Availability of data and materials
For information on how to submit an application for gaining access to EPIC data and/or biospecimens, please follow the instructions at http://epic.iarc.fr/access/index.php

Ethics approval and consent to participate
The EPIC study was approved by the ethics committees of the International Agency for Research on Cancer and the individual study centres. The Netherlands Cohort Study was approved by the institutional review boards of the Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek (TNO) Quality of Life research institute (Zeist, Netherlands) and Maastricht University (Maastricht, Netherlands). Informed consent was provided by all participants.

Consent for publication
Not applicable.

Breast Cancer Res. 2020;22(5) © 2020 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Distribution of baseline demographic characteristics and covariates in the EPIC study
		Total		Non-case		Case
		n	%	n	%	n	%
	Total	272,098	100	261,119	100	10,979	100
Age at recruitment (years)	[19.9, 40)	33,452	12	32,896	13	556	5
	[40, 45)	35,784	13	34,720	13	1064	10
	[45, 50)	52,234	19	50,102	19	2132	19
	[50, 55)	60,487	22	57,499	22	2988	27
	[55, 60)	42,506	16	40,278	15	2228	20
	[60, 65)	33,176	12	31,668	12	1508	14
	[65, 70)	10,996	4	10,580	4	416	4
	[70, 75)	2966	4	2886	1	80	1
	[75, 98.5]	497	0	490	0	7	0
Smoking status	Never	158,234	58	152,103	58	6131	56
	Former	60,085	22	57,419	22	2666	24
	Current	53,779	20	51,597	20	2182	20
Education	None/primary school	82,923	30	79,947	31	2976	27
	Technical/professional school	57,553	21	55,074	21	2479	23
	Secondary school	66,456	24	63,663	24	2793	25
	Longer education (incl. university degree)	65,166	24	62,435	24	2731	25
BMI (kg/m²)	[10.2, 20)	22,799	8	22,007	8	792	7
	[20, 23)	79,289	29	76,013	29	3276	30
	[23, 25)	55,581	20	53,238	20	2343	21
	[25, 30)	78,670	29	75,440	29	3230	29
	[30, 35)	26,452	10	25,443	10	1009	9
	[35, 77.9]	9307	3	8978	3	329	3
Physical activity	Inactive	60,140	22	57,932	22	2208	20
	Moderately inactive	94,409	35	90,456	35	3953	36
	Moderately active	75,196	28	72,163	28	3033	28
	Active	42,353	16	40,568	16	1785	16
Diabetes	No	265,318	98	254,607	98	10,711	98
Diabetes	Yes	6780	2	6512	2	268	2
Postmenopausal	No	146,620	54	141,379	54	5241	48
Postmenopausal	Yes	125,478	46	119,740	46	5738	52
Parous	No	42,130	15	40,579	16	1551	14
Parous	Yes	229,968	85	220,540	84	9428	86

Table 2. Distribution of baseline demographic characteristics and covariates in the Netherlands Cohort Study
		Non-case		Case
		n	%	n	%
	Total	1608	100	2368	100
Age at recruitment (years)	[55, 60)	628	39	898	38
	[60, 65)	544	34	869	37
	[65, 69]	436	27	601	25
Smoking status	Never	927	58	1306	55
	Former	339	21	552	23
	Current	342	21	510	22
Education	Primary school	516	32	701	30
	Lower vocational school	364	23	506	21
	Secondary, medium vocational school	573	36	923	39
	Higher vocational, university degree	155	10	238	10
BMI (kg/m²)	[14.5, 20)	81	5	77	3
	[20, 23)	377	23	511	22
	[23, 25)	457	28	633	27
	[25, 30)	555	35	931	39
	[30, 35)	118	7	181	8
	[35, 44.3]	20	1	35	1
Physical activity (non-occupational, min/day)	[0, 30]	358	22	622	26
	(30, 60]	521	32	773	33
	(60, 90]	378	24	510	22
	(90, 415]	351	22	463	20
Diabetes	Yes	57	4	74	3
Parous	Yes	292	18	479	20
Family history of breast cancer (mother/sister(s))	Yes	139	9	348	15

Authors and Disclosures

Alicia K. Heath¹*, David C. Muller¹, Piet A. van den Brandt², Nikos Papadimitriou^3,4, Elena Critselis^5,6, Marc Gunter^1,4, Paolo Vineis¹, Elisabete Weiderpass⁷, Guy Fagherazzi^8,9, Heiner Boeing¹⁰, Pietro Ferrari⁴, Anja Olsen¹¹, Anne Tjønneland^11,12, Patrick Arveux^8,13, Marie-Christine Boutron-Ruault⁸, Francesca Romana Mancini⁸, Tilman Kühn¹⁴, Renée Turzanski-Fortner¹⁴, Matthias B. Schulze^15,16, Anna Karakatsani^17,18, Paschalis Thriskos¹⁷, Antonia Trichopoulou¹⁷, Giovanna Masala¹⁹, Paolo Contiero²⁰, Fulvio Ricceri^21,22, Salvatore Panico²³, Bas Bueno-de-Mesquita^1,24–26, Marije F. Bakker²⁷, Carla H. van Gils²⁷, Karina Standahl Olsen²⁸, Guri Skeie²⁸, Cristina Lasheras²⁹, Antonio Agudo³⁰, Miguel Rodríguez-Barranco^31–34, Maria-José Sánchez^31–34, Pilar Amiano^33,35, María-Dolores Chirlaque^33,36, Aurelio Barricarte^33,37,38, Isabel Drake³⁹, Ulrika Ericson³⁹, Ingegerd Johansson⁴⁰, Anna Winkvist^41,42, Tim Key⁴³, Heinz Freisling⁴, Mathilde His⁴, Inge Huybrechts⁴, Sofia Christakoudi^1,44, Merete Ellingjord-Dale¹, Elio Riboli¹, Konstantinos K. Tsilidis^1,3† and Ioanna Tzoulaki^1,3†

¹Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, UK. ²Department of Epidemiology, Maastricht University Medical Centre, Maastricht, the Netherlands. ³Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. ⁴Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France. ⁵Proteomics Facility, Center for Systems Biology, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. ⁶Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece. ⁷International Agency for Research on Cancer, World Health Organization, Lyon, France. ⁸Center of Research in Epidemiology and Population Health (CESP), Inserm U1018, Paris-South Paris-Saclay University, Gustave Roussy, Villejuif, France. ⁹Department of Population Health, Luxembourg Institute of Health, Strassen, Luxembourg. ¹⁰Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. ¹¹Danish Cancer Society Research Center, Copenhagen, Denmark. ¹²University of Copenhagen, Copenhagen, Denmark. ¹³Breast and Gynaecologic Cancer Registry of Côte d'Or, Georges-François Leclerc Cancer Centre, UNICANCER, Dijon, France. ¹⁴Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. ¹⁵Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. ¹⁶Institute of Nutritional Sciences, University of Potsdam, Nuthetal, Germany. ¹⁷Hellenic Health Foundation, Athens, Greece. ¹⁸2nd Pulmonary Medicine Department, School of Medicine, National and Kapodistrian University of Athens, "ATTIKON" University Hospital, Haidari, Greece. ¹⁹Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy. ²⁰Environmental Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy. ²¹Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. ²²Unit of Epidemiology, Regional Health Service ASL TO3, Grugliasco, Italy. ²³Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. ²⁴Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. ²⁵Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. ²⁶Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia. ²⁷Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. ²⁸Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway. ²⁹Functional Biology Department, School of Medicine, University of Oviedo, Asturias, Spain. ³⁰Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute – IDIBELL, L'Hospitalet of Llobregat, Barcelona, Spain. ³¹Andalusian School of Public Health (EASP), Granada, Spain. ³²Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. ³³CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain. ³⁴Universidad de Granada (UGR), Granada, Spain. ³⁵Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain. ³⁶Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain. ³⁷Navarra Public Health Institute, Pamplona, Spain. ³⁸Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. ³⁹Department of Clinical Sciences in Malmö, Lund University, Malmö, Sweden. ⁴⁰Department of Odontology, Umeå University, Umeå, Sweden. ⁴¹Department of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. ⁴²Department of Public Health and Clinical Medicine, Section of Sustainable Health, Umeå University, Umeå, Sweden. ⁴³Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. ⁴⁴MRC Centre for Transplantation, King's College London, London, UK.

* Correspondence
a.heath@imperial.ac.uk

^†Konstantinos K. Tsilidis and Ioanna Tzoulaki contributed equally to this work.

Authors' contributions
DCM, KTT, and IT designed the research; DCM analysed the data and performed the statistical analysis; AKH and DCM wrote the paper; KTT had the primary responsibility for final content. All authors read and approved the final manuscript.

Competing interests
The authors declare that they have no competing interests.