title: Promoter CpG island methylation in ion transport mechanisms and associated dietary intakes jointly influence the risk of clear-cell renal cell cancer.
abstract: Sodium intake, but not potassium or fluid intake, has been associated with higher renal cell cancer (RCC) risk. However, risk factors may differ by molecular subtypes of the tumour. In renal physiology, electrolyte and water homeostasis is facilitated by ion transport mechanisms (ITM). Aberrant regulation of ITM genes, for example by promoter CpG island methylation, may modify associations between sodium, potassium and fluid intake and RCC risk.
  
  
  
  We identified ARHGDIG , ATP1A1 , SCNN1B and SLC8A3 as ITM genes exhibiting RCC-specific promoter methylation and down-regulation. Methylation-specific polymerase chain reaction (PCR) was used to analyse promoter CpG island methylation in tumour DNA of 453 RCC cases from the Netherlands Cohort Study ( n = 120 852) after 20.3 years of follow-up. Diet was measured at baseline using food-frequency questionnaires. Cox regression analyses were restricted to clear-cell (cc)RCC ( n = 306) and stratified by tumours with no, low (1 gene) and high (≥ 2 genes) methylation.
  
  
  
  Sodium intake (high vs low) increased ccRCC risk particularly in tumours with a high methylation index: hazard ratio (HR) [95% confidence interval (CI)]: 2.04 (1.16-3.58), whereas heterogeneity across the methylation index was not significant ( P -heterogeneity = 0.26). Potassium intake was differentially associated with ccRCC risk ( P -heterogeneity = 0.008); the risk for high (vs low) potassium intake was low for unmethylated tumours [HR (95% CI): 0.60 (0.36-1.01)], but high for tumours with a high methylation index [HR (95% CI): 1.60 (0.96-2.65)]. Risks similarly differed for fluid intake, though not significantly ( P -heterogeneity = 0.54).
  
  
  
  Our findings suggest for the first time that dietary intakes are differentially associated with ccRCC risk according to molecular subtypes defined by ITM gene-specific promoter methylation.
authors: Department of Epidemiology.
authors: Ivette Ag
authors: IA
authors: Deckers
authors: Department of Pathology.
authors: Manon
authors: M
authors: van Engeland
authors: Department of Epidemiology.
authors: Piet A
authors: PA
authors: van den Brandt
authors: Department of Pathology.
authors: Leander
authors: L
authors: Van Neste
authors: Department of Medical Oncology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.
authors: Patricia Mmb
authors: PM
authors: Soetekouw
authors: Department of Medical Oncology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.
authors: Maureen Jb
authors: MJ
authors: Aarts
authors: Department of Pathology.|Department of Pathology, Antwerp University Hospital, Antwerp, Belgium.
authors: Marcella Mll
authors: MM
authors: Baldewijns
authors: Department of Epidemiology.|Department of Medical Informatics, Uniklinik RWTH Aachen University, Aachen, Germany.
authors: András P
authors: AP
authors: Keszei
authors: Department of Epidemiology.
authors: Leo J
authors: LJ
authors: Schouten
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D006801:Humans; D017136:Ion Transport; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D017419:Potassium, Dietary / Q000009:adverse effects; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*
chemical_list: D017419:Potassium, Dietary; D017673:Sodium Chloride, Dietary
keywords: Promoter CpG island methylation; clear-cell renal cell cancer risk; dietary intakes; ion transport mechanisms; prospective cohort