{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T23:56:31Z","timestamp":1783468591140,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pmed.1003786","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T00:00:00Z","timestamp":1633564800000}}],"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000321","name":"World Cancer Research Fund","doi-asserted-by":"crossref","award":["2014\/1193"],"award-info":[{"award-number":["2014\/1193"]}],"id":[{"id":"10.13039\/501100000321","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"crossref","award":["313010"],"award-info":[{"award-number":["313010"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cancer Research UK Programme Grant","award":["C18281\/A19169"],"award-info":[{"award-number":["C18281\/A19169"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["202802\/Z\/16\/Z"],"award-info":[{"award-number":["202802\/Z\/16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MC_PC_13048"],"award-info":[{"award-number":["MC_PC_13048"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L00002\/1"],"award-info":[{"award-number":["MR\/L00002\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["115372"],"award-info":[{"award-number":["115372"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013342","name":"NIHR Imperial Biomedical Research Centre","doi-asserted-by":"publisher","award":["BRC-1215-20014"],"award-info":[{"award-number":["BRC-1215-20014"]}],"id":[{"id":"10.13039\/501100013342","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods and findings<\/jats:title>\n<jats:p>We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case\u2013control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, <jats:italic>p<\/jats:italic> = 2.6 \u00d7 10<jats:sup>\u22128<\/jats:sup>). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, <jats:italic>p<\/jats:italic> = 1.6 \u00d7 10<jats:sup>\u22125<\/jats:sup>), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some\u2014but not all\u2014metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., \u22120.17 SD change [\u00df<jats:sub>BMI<\/jats:sub>] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0\/18:2) levels per SD change in BMI, <jats:italic>p<\/jats:italic> = 3.4 \u00d7 10<jats:sup>\u22125<\/jats:sup>). BMI was also associated with increased levels of glutamate (\u00df<jats:sub>BMI<\/jats:sub>: 0.12, <jats:italic>p<\/jats:italic> = 1.5 \u00d7 10<jats:sup>\u22123<\/jats:sup>). While our results were robust across the participating studies, they were limited to study participants of European descent, and it will, therefore, be important to evaluate if our findings can be generalised to populations with different genetic backgrounds.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This study suggests a potentially important role of the blood metabolome in kidney cancer aetiology by highlighting a wide range of metabolites associated with the risk of developing kidney cancer and the extent to which changes in levels of these metabolites are driven by BMI\u2014the principal modifiable risk factor of kidney cancer.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pmed.1003786","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T18:29:50Z","timestamp":1632162590000},"page":"e1003786","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":39,"title":["The blood metabolome of incident kidney cancer: A case\u2013control study nested within the MetKid consortium"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9652-2430","authenticated-orcid":true,"given":"Florence","family":"Guida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7938-127X","authenticated-orcid":true,"given":"Vanessa 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Engelmann","year":"2004","journal-title":"Biochem Soc Trans"},{"issue":"1","key":"pmed.1003786.ref049","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12944-018-0685-9","article-title":"Plasmalogen lipids: functional mechanism and their involvement in gastrointestinal cancer","volume":"17","author":"MCF Messias","year":"2018","journal-title":"Lipids Health Dis"},{"issue":"7","key":"pmed.1003786.ref050","doi-asserted-by":"crossref","first-page":"e6261","DOI":"10.1371\/journal.pone.0006261","article-title":"Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients","volume":"4","author":"J Graessler","year":"2009","journal-title":"PLoS ONE"},{"issue":"2","key":"pmed.1003786.ref051","doi-asserted-by":"crossref","first-page":"e218","DOI":"10.1371\/journal.pone.0000218","article-title":"Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects\u2014a monozygotic twin 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Oresic","year":"2008","journal-title":"J Exp Med"},{"issue":"10","key":"pmed.1003786.ref055","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1007\/s00125-013-2981-2","article-title":"Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids","volume":"56","author":"M Oresic","year":"2013","journal-title":"Diabetologia"},{"issue":"12","key":"pmed.1003786.ref056","doi-asserted-by":"crossref","first-page":"3957","DOI":"10.18632\/aging.101685","article-title":"Integrated multi-omics characterization reveals a distinctive metabolic signature and the role of NDUFA4L2 in promoting angiogenesis, chemoresistance, and mitochondrial dysfunction in clear cell renal cell carcinoma","volume":"10","author":"G Lucarelli","year":"2018","journal-title":"Aging (Albany NY)."},{"key":"pmed.1003786.ref057","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s12986-015-0059-5","article-title":"Associations among the plasma amino acid profile, obesity, and glucose metabolism in Japanese adults with normal glucose tolerance","volume":"13","author":"C Takashina","year":"2016","journal-title":"Nutr Metab (Lond)."},{"issue":"8","key":"pmed.1003786.ref058","doi-asserted-by":"crossref","first-page":"E736","DOI":"10.1152\/ajpendo.00231.2015","article-title":"Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk","volume":"309","author":"MM Boulet","year":"2015","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"pmed.1003786.ref059","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/978-3-319-77736-8_2","article-title":"Glutamine Metabolism in Cancer","volume":"1063","author":"T Li","year":"2018","journal-title":"Adv Exp Med Biol"},{"issue":"21","key":"pmed.1003786.ref060","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1073\/pnas.1507228112","article-title":"MYC oncogene overexpression drives renal cell carcinoma in a mouse model through glutamine metabolism","volume":"112","author":"EH Shroff","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"pmed.1003786.ref061","doi-asserted-by":"crossref","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of cancer metabolism","volume":"2","author":"RJ DeBerardinis","year":"2016","journal-title":"Sci Adv"},{"issue":"1","key":"pmed.1003786.ref062","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1186\/s12916-019-1408-4","article-title":"Prospective analysis of circulating metabolites and breast cancer in EPIC.","volume":"17","author":"M His","year":"2019","journal-title":"BMC Med"},{"issue":"3","key":"pmed.1003786.ref063","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/ijc.31341","article-title":"Prospective study of blood metabolites associated with colorectal cancer risk","volume":"143","author":"X Shu","year":"2018","journal-title":"Int J 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