Promoter CpG island methylation in ion transport mechanisms and associated dietary intakes jointly influence the risk of clear-cell renal cell cancer

Ivette A. G. Deckers, Manon van Engeland, Piet A. van den Brandt, Leander Van Neste, Patricia M. M. B. Soetekouw, Maureen J. B. Aarts, Marcella M. L. L. Baldewijns, Andras P. Keszei, Leo J. Schouten*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Background: 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 sub-types 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Original languageEnglish
Pages (from-to)622-631
Number of pages10
JournalInternational Journal of Epidemiology
Issue number2
Publication statusPublished - Apr 2017


  • Promoter CpG island methylation
  • clear-cell renal cell cancer risk
  • ion transport mechanisms
  • dietary intakes
  • prospective cohort

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