Prospective Analysis of Circulating Metabolites and Endometrial Cancer Risk

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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References

Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G . Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids. 2013; 45(3):463-77. DOI: 10.1007/s00726-013-1493-1. View

Soerjomataram I, Shield K, Marant-Micallef C, Vignat J, Hill C, Rogel A . Cancers related to lifestyle and environmental factors in France in 2015. Eur J Cancer. 2018; 105:103-113. DOI: 10.1016/j.ejca.2018.09.009. View

Schiffmann S, Sandner J, Birod K, Wobst I, Angioni C, Ruckhaberle E . Ceramide synthases and ceramide levels are increased in breast cancer tissue. Carcinogenesis. 2009; 30(5):745-52. DOI: 10.1093/carcin/bgp061. View

Gunter M, Hoover D, Yu H, Wassertheil-Smoller S, Manson J, Li J . A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2008; 17(4):921-9. PMC: 3090086. DOI: 10.1158/1055-9965.EPI-07-2686. View

Floegel A, Wientzek A, Bachlechner U, Jacobs S, Drogan D, Prehn C . Linking diet, physical activity, cardiorespiratory fitness and obesity to serum metabolite networks: findings from a population-based study. Int J Obes (Lond). 2014; 38(11):1388-96. PMC: 4229626. DOI: 10.1038/ijo.2014.39. View

Islami F, Sauer A, Miller K, Siegel R, Fedewa S, Jacobs E . Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin. 2017; 68(1):31-54. DOI: 10.3322/caac.21440. View

Fikri A, Smyth R, Kumar V, Al-Abadla Z, Abusnana S, Munday M . Pre-diagnostic biomarkers of type 2 diabetes identified in the UAE's obese national population using targeted metabolomics. Sci Rep. 2020; 10(1):17616. PMC: 7572402. DOI: 10.1038/s41598-020-73384-7. View

Schmidt J, Fensom G, Rinaldi S, Scalbert A, Appleby P, Achaintre D . Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case-control sets from EPIC. Int J Cancer. 2019; 146(3):720-730. PMC: 6916595. DOI: 10.1002/ijc.32314. View

Audet-Delage Y, Villeneuve L, Gregoire J, Plante M, Guillemette C . Identification of Metabolomic Biomarkers for Endometrial Cancer and Its Recurrence after Surgery in Postmenopausal Women. Front Endocrinol (Lausanne). 2018; 9:87. PMC: 5857535. DOI: 10.3389/fendo.2018.00087. View

10.

Cavus E, Karakas M, Ojeda F, Kontto J, Veronesi G, Ferrario M . Association of Circulating Metabolites With Risk of Coronary Heart Disease in a European Population: Results From the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium. JAMA Cardiol. 2019; 4(12):1270-1279. PMC: 6822093. DOI: 10.1001/jamacardio.2019.4130. View

11.

Lortet-Tieulent J, Ferlay J, Bray F, Jemal A . International Patterns and Trends in Endometrial Cancer Incidence, 1978-2013. J Natl Cancer Inst. 2017; 110(4):354-361. DOI: 10.1093/jnci/djx214. View

12.

Floegel A, Stefan N, Yu Z, Muhlenbruch K, Drogan D, Joost H . Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes. 2012; 62(2):639-48. PMC: 3554384. DOI: 10.2337/db12-0495. View

13.

Becker S, Dossus L, Kaaks R . Obesity related hyperinsulinaemia and hyperglycaemia and cancer development. Arch Physiol Biochem. 2009; 115(2):86-96. DOI: 10.1080/13813450902878054. View

14.

Carayol M, Licaj I, Achaintre D, Sacerdote C, Vineis P, Key T . Reliability of Serum Metabolites over a Two-Year Period: A Targeted Metabolomic Approach in Fasting and Non-Fasting Samples from EPIC. PLoS One. 2015; 10(8):e0135437. PMC: 4537119. DOI: 10.1371/journal.pone.0135437. View

15.

Floegel A, Drogan D, Wang-Sattler R, Prehn C, Illig T, Adamski J . Reliability of serum metabolite concentrations over a 4-month period using a targeted metabolomic approach. PLoS One. 2011; 6(6):e21103. PMC: 3115978. DOI: 10.1371/journal.pone.0021103. View

16.

Reuter S, Evans A, Chace D, Fornasini G . Determination of the reference range of endogenous plasma carnitines in healthy adults. Ann Clin Biochem. 2008; 45(Pt 6):585-92. DOI: 10.1258/acb.2008.008045. View

17.

Bienias K, Fiedorowicz A, Sadowska A, Prokopiuk S, Car H . Regulation of sphingomyelin metabolism. Pharmacol Rep. 2016; 68(3):570-81. DOI: 10.1016/j.pharep.2015.12.008. View

18.

Park S, Sadanala K, Kim E . A Metabolomic Approach to Understanding the Metabolic Link between Obesity and Diabetes. Mol Cells. 2015; 38(7):587-96. PMC: 4507023. DOI: 10.14348/molcells.2015.0126. View

19.

Mahajan U, Varma V, Huang C, An Y, Tanaka T, Ferrucci L . Blood Metabolite Signatures of Metabolic Syndrome in Two Cross-Cultural Older Adult Cohorts. Int J Mol Sci. 2020; 21(4). PMC: 7072935. DOI: 10.3390/ijms21041324. View

20.

Cheng S, Rhee E, Larson M, Lewis G, McCabe E, Shen D . Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation. 2012; 125(18):2222-31. PMC: 3376658. DOI: 10.1161/CIRCULATIONAHA.111.067827. View