Association of FOXO3 Blood DNA Methylation with Cancer Risk, Cancer Survival, and Mortality.

Chenglong Yu,Pierre-Antoine Dugué,John L Hopper,Enes Makalic,Daniel D Buchanan,Daniel Schmidt,Ee Ming Wong,Melissa C Southey,Jihoon Eric Joo,Allison M Hodge,Graham G Giles

doi:10.3390/cells10123384

Abstract

Genetic variants in FOXO3 are associated with longevity. Here, we assessed whether blood DNA methylation at FOXO3 was associated with cancer risk, survival, and mortality. We used data from eight prospective case–control studies of breast (n = 409 cases), colorectal (n = 835), gastric (n = 170), kidney (n = 143), lung (n = 332), prostate (n = 869), and urothelial (n = 428) cancer and B-cell lymphoma (n = 438). Case–control pairs were matched on age, sex, country of birth, and smoking (lung cancer study). Conditional logistic regression was used to assess associations between cancer risk and methylation at 45 CpGs of FOXO3 included on the HumanMethylation450 assay. Mixed-effects Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations with cancer survival (total n = 2286 deaths). Additionally, using data from 1088 older participants, we assessed associations of FOXO3 methylation with overall and cause-specific mortality (n = 354 deaths). Methylation at a CpG in the first exon region of FOXO3 (6:108882981) was associated with gastric cancer survival (HR = 2.39, 95% CI: 1.60–3.56, p = 1.9 × 10−5). Methylation at three CpGs in TSS1500 and gene body was associated with lung cancer survival (p < 6.1 × 10−5). We found no evidence of associations of FOXO3 methylation with cancer risk and mortality. Our findings may contribute to understanding the implication of FOXO3 in longevity.

Highlights

Genetic variation within the gene FOXO3 was first shown to be strongly associated with lifespan using C. elegans models [1,2,3,4]
We considered associations to be significant after Bonferroni correction for multiple comparisons across four single nucleotide polymorphisms (SNP) and 45 cytosine-guanine dinucleotide (CpG) sites (p = 0.05/(45 × 4) = 2.78 × 10−4)
The Pearson correlation matrix of methylation values of the 3481 controls at the 45 CpGs across FOXO3 is shown in Figure 2 and Table S2, showing generally weak correlations, typically lower than 0.3; these were null between promoter regions (TSS1500, TSS200 and 5 UTR) and the first exon, positive within the promoter and gene body regions, and negative between promoter and gene body regions

Summary

Introduction

Genetic variation within the gene FOXO3 was first shown to be strongly associated with lifespan using C. elegans models [1,2,3,4]. The rs2802292 minor G-allele has been demonstrated to have protective effects on several specific age-related disorders, such as lower incidence of cancer and heart disease, in particular, coronary artery disease, and fewer bone fractures [11]. Epigenetic changes such as DNA methylation are thought to play a major role in tumourigenesis through their influence on various mechanisms, in particular, gene expression and genomic stability. The extent to which constitutional methylation changes may affect gene expression is not fully understood, there is value in assessing the association of blood DNA methylation with risk of and survival from cancer, as a major disease contributing to reduced longevity

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Conclusion