Abstract
BACKGROUND: Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation.
METHODS: To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively.
RESULTS: Higher sRAGE concentrations were inversely associated with colorectal cancer (ORQ5vs.Q1, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (ORQ5vs.Q1, 1.00; 95% CI, 0.68-1.48; P heterogeneity for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99).
CONCLUSIONS: Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within ADAM10 gene, pertaining to RAGE shedding, was associated with colorectal cancer risk.
IMPACT: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.
| Originalsprache | Englisch |
|---|---|
| Seiten (von - bis) | 182-192 |
| Seitenumfang | 11 |
| Fachzeitschrift | Cancer Epidemiology, Biomarkers & Prevention |
| Jahrgang | 30 |
| Ausgabenummer | 1 |
| DOIs | |
| Publikationsstatus | Veröffentlicht - Jan. 2021 |
| Extern publiziert | Ja |
Fördermittel
preparing the databases and providing technical support pertaining to the data analysis, along with Ms. Audrey Brunat-Manquat for her assistance with the laboratory analyses for sRAGE. The coordination of the EPIC study was financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts were supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G\u00E9n\u00E9rale de l\u2019Education Nationale, and Institut National de la Sant\u00E9et de la Recherche M\u00E9dicale (INSERM, France); German Cancer Aid, German Cancer Research Center (DKFZ), and Federal Ministry of Education and Research (BMBF, Germany); Italian Association for Research on Cancer (AIRC), National Research Council, Associa-zione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS) Ragusa, Associazione Volontari Italiani Sangu (AVIS) Ragusa, and the Sicilian Government (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), and Statistics Netherlands (the Netherlands); Health Research Fund (FIS); Regional Governments of Andaluc\u00EDa, Asturias, Basque Country, Murcia (No. 6236) and Navarra; the Centro de Investigaci\u00F3n Biom\u00E9dica en Red en Epidemiolog\u00EDa y Salud P\u00FAblica and Instituto de Salud Carlos II (ISCIII RETIC, RD06/0020, Spain); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc\u00EDa, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain); Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Ska\u00B0ne and V\u20ACasterbotten (Sweden); Cancer Research UK, Medical Research The funding for this work (WCRF 2015/1391, to principal investigator, M. Jenab) was obtained from Wereld Kanker Onderzoek Fonds, as part of the World Cancer Research Fund International grant program. The authors thank the EPIC study participants and staff for their valuable contribution to this research. The authors especially thank Mr. Bertrand Hemon and Dr. Aurelie Moskal for their support in preparing the databases and providing technical support pertaining to the data analysis, along with Ms. Audrey Brunat-Manquat for her assistance with the laboratory analyses for sRAGE. The coordination of the EPIC study was financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts were supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle G?n?rale de l'Education Nationale, and Institut National de la Sant? et de la Recherche M?dicale (INSERM, France); German Cancer Aid, German Cancer Research Center (DKFZ), and Federal Ministry of Education and Research (BMBF, Germany); Italian Association for Research on Cancer (AIRC), National Research Council, Associazione Iblea per la Ricerca Epidemiologica (AIRE-ONLUS) Ragusa, Associazione Volontari Italiani Sangu (AVIS) Ragusa, and the Sicilian Government (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), and Statistics Netherlands (the Netherlands); Health Research Fund (FIS); Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia (No. 6236) and Navarra; the Centro de Investigaci?n Biom?dica en Red en Epidemiolog?a y Salud P?blica and Instituto de Salud Carlos II (ISCIII RETIC, RD06/0020, Spain); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andaluc?a, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain); Swedish Cancer Society, Swedish Scientific Council, and Regional Government of Sk?ne and V?sterbotten (Sweden); Cancer Research UK, Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and the Wellcome Trust (United Kingdom). This work was also supported by grants from Cancer Research UK (14136 to EPIC-Norfolk; and C570/A16491, C8221/A19170, and C8221/A29017 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk and MR/M012190/1 to EPIC-Oxford, United Kingdom). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) has received funding from the Medical Research Council (MR/N003284/1 and MC-UU-12015/1) and Cancer Research UK (C864/A14136). The authors are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge (Cambridge, England) who helped enable this research. This work was partially financially supported by the Fondation de France (FDF, grant no. 00081166 to H. Freisling and R. Cordova and FDF grant no. 00089811 to A.-L. May?n). The funding for this work (WCRF 2015/1391, to principal investigator, M. Jenab) was obtained from Wereld Kanker Onderzoek Fonds, as part of the World Cancer Research Fund International grant program. The authors thank the EPIC study participants and staff for their valuable contribution to this research. The authors especially thank Mr. Bertrand Hemon and Dr. Aurelie Moskal for their support in
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