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Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival.

ABSTRACT: The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival.The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested within the Melbourne Collaborative Cohort Study (MCCS). Plasma concentrations of vitamin B2, vitamin B6, folate, vitamin B12, methionine and homocysteine were measured in prediagnostic samples and evaluated with respect to RCC risk using conditional and unconditional logistic regression models, and to all-cause mortality in RCC cases using Cox regression models. All statistical tests were two-sided.EPIC participants with higher plasma concentrations of vitamin B6 had lower risk of RCC, the odds ratio comparing the 4(th) and 1(st) quartiles (OR4vs1) being 0.40 95% confidence interval [CI] = 0.28 to 0.57, P trend < .001. We found similar results after adjusting for potential confounders (adjusted P trend < .001). In survival analysis, the hazard ratio for all-cause mortality in RCC cases when comparing the 4(th) and 1(st) quartiles (HR4vs1) of vitamin B6 was 0.57 (95% CI = 0.37 to 0.87, P trend < .001). Subsequent replication of these associations within the MCCS yielded very similar results for both RCC risk (OR4vs1 = 0.47, 95% CI = 0.23 to 0.99, P trend = .07) and all-cause mortality (HR4vs1 = 0.56, 95% CI = 0.27 to 1.17, P trend = .02). No association was evident for the other measured biomarkers.Study participants with higher circulating concentrations of vitamin B6 had lower risk of RCC and improved survival following diagnosis in two independent cohorts.

SUBMITTER: Johansson M

PROVIDER: S-EPMC4273895 | biostudies-other | 2014 Dec

REPOSITORIES: biostudies-other

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Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival.

Johansson Mattias M Fanidi Anouar A Muller David C DC Bassett Julie K JK Midttun Øivind Ø Vollset Stein Emil SE Travis Ruth C RC Palli Domenico D Mattiello Amalia A Sieri Sabina S Trichopoulou Antonia A Lagiou Pagona P Trichopoulos Dimitrios D Ljungberg Börje B Hallmans Göran G Weiderpass Elisabete E Skeie Guri G González Carlos A CA Dorronsoro Miren M Peeters Petra H PH Bueno-de-Mesquita H Bas HB Ros Martine M MM Boutron Ruault Marie-Christine MC Fagherazzi Guy G Clavel Françoise F Sánchez María-José MJ Gurrea Aurelio Barricarte AB Navarro Carmen C Quiros J Ramon JR Overvad Kim K Tjønneland Anne A Aleksandrova Krassimira K Vineis Paolo P Gunter Marc J MJ Kaaks Rudolf R Giles Graham G Relton Caroline C Riboli Elio E Boeing Heiner H Ueland Per Magne PM Severi Gianluca G Brennan Paul P

Journal of the National Cancer Institute 20141105 12

<h4>Background</h4>The etiology of renal cell carcinoma (RCC) is only partially understood, but a metabolic component appears likely. We investigated biomarkers of one-carbon metabolism and RCC onset and survival.<h4>Methods</h4>The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 385747 participants with blood samples between 1992 and 2000, and this analysis included 556 RCC case-control pairs. A subsequent replication study included 144 case-control pairs nested wi ...[more]

PMID: 25376861

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Project description:Folate-mediated one-carbon metabolism is essential for DNA synthesis, repair, and methylation. Perturbations in one-carbon metabolism have been implicated in increased risk of some cancers and may also affect inflammatory processes. We investigated these interrelated pathways to understand their relation. The objective was to explore associations between inflammation and biomarkers of nutritional status and one-carbon metabolism. In a cross-sectional study in 1976 women selected from the Women's Health Initiative Observational Study, plasma vitamin B-6 [pyridoxal-5'-phosphate (PLP)], plasma vitamin B-12, plasma folate, and RBC folate were measured as nutritional biomarkers; serum C-reactive protein (CRP) and serum amyloid A (SAA) were measured as biomarkers of inflammation; and homocysteine and cysteine were measured as integrated biomarkers of one-carbon metabolism. Student's t, chi-square, and Spearman rank correlations, along with multiple linear regressions, were used to explore relations between biomarkers; additionally, we tested stratification by folic acid fortification period and multivitamin use. With the use of univariate analysis, plasma PLP was the only nutritional biomarker that was modestly significantly correlated with serum CRP and SAA (? = -0.22 and -0.12, respectively; P < 0.0001). Homocysteine (?mol/L) showed significant inverse correlations with all nutritional biomarkers (ranging from ? = -0.30 to ? = -0.46; all P < 0.0001). With the use of multiple linear regression, plasma PLP, RBC folate, homocysteine, and cysteine were identified as independent predictors of CRP; and PLP, vitamin B-12, RBC folate, and homocysteine were identified as predictors of SAA. When stratified by folic acid fortification period, nutrition-homocysteine correlations were generally weaker in the postfortification period, whereas associations between plasma PLP and serum CRP increased. Biomarkers of inflammation are associated with PLP, RBC folate, and homocysteine in women. The connection between the pathways needs to be further investigated and causality established. The trial is registered at clinicaltrials.gov as NCT00000611.

Project description:Purpose:Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults. Exosomes are membrane-enclosed extracellular vesicles, and exosomal RNA can be a biomarker for cancer diagnosis and prognosis in RCC patients. We aim to identify differences in miRNA expression profiles in peripheral blood exosomes between RCC patients and healthy subjects as well as to investigate novel markers of RCC. Methods:We performed exosomal miRNA sequencing of plasma samples obtained from five RCC patients and five control subjects, subsequently 22 RCC patients and 16 control subjects were investigated using qPCR to confirm the differential miRNA which from plasma exosomal RNA sequencing. ROC curves were constructed to assess the diagnostic accuracy of exosomal miRNAs as diagnostic biomarkers of RCC. Results:Exosomes were isolated with the exoeasy maxi kit and confirmed using TEM and NTA. They have a spherical structure with a diameter of approximately 40-180 nm. The exosomal miRNA sequence results showed that a total of 2357 miRNAs were detected, and 245 miRNAs were differentially expressed between RCC patients and healthy controls (p<0.001, average counts >5, log|fc|>1). Further analysis revealing that, versus the control, 17 miRNAs are up-regulated and 5 miRNAs are down-regulated under selection conditions with average miRNAs counts >100. qPCR was performed using 38 subjects-the results showed that the expression levels of hsa-mir-149-3p and hsa-mir-424-3p were upregulated; the expression levels of hsa-mir-92a-1-5p were significantly downregulated in the plasma exosomes of RCC. For diagnosis of RCC, the AUC of hsa-mir-92a-1-5p, hsa-mir-149-3p and hsa-mir-424-3p was 0.8324, 0.7188 and 0.7727, with the sensitivity of 0.875, 0.750 and 0.750, and the specificity of 0.773,0.727 and 0.818, respectively, at the best cutoff value. Conclusion:Our study revealed that the expression levels of hsa-mir-92a-1-5p, hsa-mir-149-3p and hsa-mir-424-3p were significantly abnormal in RCC patients, which may be novel biomarkers for RCC diagnosis.

Dataset Information

Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival.

Publications

Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival.

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