Prospective analysis of circulating metabolites and endometrial cancer risk

Laure Dossus; Eirini Kouloura; Carine Biessy; Vivian Viallon; Alexandros P Siskos; Niki Dimou; Sabina Rinaldi; Melissa A Merritt; Naomi Allen; Renee Fortner; Rudolf Kaaks; Elisabete Weiderpass; Inger T Gram; Joseph A Rothwell; Lucie Lécuyer; Gianluca Severi; Matthias B Schulze; Therese Haugdahl Nøst; Marta Crous-Bou; Maria-Jose Sánchez; Pilar Amiano; Sandra M Colorado-Yohar; Aurelio Barricarte Gurrea; Julie A Schmidt; Domenico Palli; Claudia Agnoli; Rosario Tumino; Carlotta Sacerdote; Amalia Mattiello; Roel Vermeulen; Alicia K Heath; Sofia Christakoudi; Konstantinos K Tsilidis; Ruth C Travis; Marc J Gunter; Hector C Keun

doi:10.1016/j.ygyno.2021.06.001

Prospective analysis of circulating metabolites and endometrial cancer risk

Gynecol Oncol. 2021 Aug;162(2):475-481. doi: 10.1016/j.ygyno.2021.06.001. Epub 2021 Jun 5.

Authors

Laure Dossus¹, Eirini Kouloura², Carine Biessy³, Vivian Viallon³, Alexandros P Siskos⁴, Niki Dimou³, Sabina Rinaldi³, Melissa A Merritt⁵, Naomi Allen⁶, Renee Fortner⁷, Rudolf Kaaks⁷, Elisabete Weiderpass⁸, Inger T Gram⁹, Joseph A Rothwell¹⁰, Lucie Lécuyer¹⁰, Gianluca Severi¹¹, Matthias B Schulze¹², Therese Haugdahl Nøst⁹, Marta Crous-Bou¹³, Maria-Jose Sánchez¹⁴, Pilar Amiano¹⁵, Sandra M Colorado-Yohar¹⁶, Aurelio Barricarte Gurrea¹⁷, Julie A Schmidt¹⁸, Domenico Palli¹⁹, Claudia Agnoli²⁰, Rosario Tumino²¹, Carlotta Sacerdote²², Amalia Mattiello²³, Roel Vermeulen²⁴, Alicia K Heath²⁵, Sofia Christakoudi²⁶, Konstantinos K Tsilidis²⁷, Ruth C Travis¹⁸, Marc J Gunter³, Hector C Keun⁴

Affiliations

¹ Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France. Electronic address: dossusl@iarc.fr.
² Cancer Metabolism and Systems Toxicology Group, Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK; European Food Safety Authority, Via Carlo Magno 1A, 43126 Parma, Italy.
³ Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France.
⁴ Cancer Metabolism and Systems Toxicology Group, Division of Cancer, Department of Surgery and Cancer, Imperial College, London, UK.
⁵ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
⁶ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁸ Office of the Director, International Agency for Research on Cancer, Lyon, France.
⁹ Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Troms, Norway.
¹⁰ Centre for Research in Epidemiology and Population Health, CESP, Université Paris-Saclay, UVSQ, Inserm U1018, Villejuif, France; Gustave Roussy, Villejuif, France.
¹¹ Centre for Research in Epidemiology and Population Health, CESP, Université Paris-Saclay, UVSQ, Inserm U1018, Villejuif, France; Gustave Roussy, Villejuif, France; Department of Statistics, Computer Science and Applications "G. Parenti" (DISIA), University of Florence, Italy.
¹² Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
¹³ Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO), Barcelona, Spain; Nutrition and Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston,USA.
¹⁴ Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
¹⁵ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Public Health Division of Gipuzkoa, BioDonostia Research Institute, Donostia-San Sebastian, Spain.
¹⁶ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain; Research Group on Demography and Health, National Faculty of Public Health, University of Antioquia, Medellín, Colombia.
¹⁷ Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarra Public Health Institute, Pamplona, Spain; Navarra Institute for Health Research (IdiSNA) Pamplona, Spain.
¹⁸ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
¹⁹ Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Cancer Risk Factors and Life-Style Epidemiology Unit, Florence, Italy.
²⁰ Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milano, Italy.
²¹ Cancer Registry and Histopathology Department, Provincial Health Authority (ASP) Ragusa, Italy.
²² Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.
²³ Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
²⁴ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.
²⁵ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
²⁶ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; MRC Centre for Transplantation, King's College London, London, UK.
²⁷ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Abstract

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_1SD: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR_1SD: 0.89, 95% CI: 0.80-0.99; OR_1SD: 0.89, 95% CI: 0.79-1.00 and OR_1SD: 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_1SD: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR_1SD: 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.

Keywords: Amino acids; Endometrial cancer; Lipids; Metabolomics; Obesity.

Publication types

Multicenter Study
Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Biomarkers, Tumor / blood*
Biomarkers, Tumor / metabolism
Body Mass Index
Carnitine / blood
Carnitine / metabolism
Case-Control Studies
Endometrial Neoplasms / blood
Endometrial Neoplasms / diagnosis*
Endometrial Neoplasms / epidemiology
Endometrial Neoplasms / metabolism
Female
Glycine / blood
Glycine / metabolism
Humans
Metabolomics
Middle Aged
Prospective Studies
Risk Factors
Serine / blood
Serine / metabolism
Sphingomyelins / blood
Sphingomyelins / metabolism

Substances

Biomarkers, Tumor
Sphingomyelins
Serine
Carnitine
Glycine

Abstract

Publication types

MeSH terms

Substances

Grants and funding