Characterization of the rs2802292 SNP identifies FOXO3Aas a modifier locus predicting cancer risk in patients with PJS and PHTS hamartomatous polyposis syndromes

Abstract

BackgroundHamartomatous polyposis syndromes (HPS) are inherited conditions associated with high cancer risk. They include the Peutz-Jeghers and the PTEN hamartoma tumor syndromes, which are caused by mutations in the LKB1 and PTEN genes, respectively. Estimation of cancer risk is crucial in order to optimize surveillance, but no prognostic markers are currently available for these conditions. Our study relies on a ‘signal transduction’ hypothesis based on the crosstalk between LKB1/AMPK and PI3K/PTEN/Akt signaling at the level of the tumor suppressor protein FoxO3A. Interestingly, the FOXO3A rs2802292 G-allele was shown to be associated with longevity, reduced risk of aging-related diseases and increased expression of FoxO3A mRNA.MethodsWe typed rs2802292 in 150 HPS unrelated patients and characterized the expression of FoxO3A by quantitative PCR and immunoblot analysis in human intestinal cell lines.ResultsWe found a significantly higher risk for malignancies in females and TT genotype carriers compared to patients having at least one G-allele. Subgroup analysis for each HPS syndrome revealed a G-allele-associated beneficial effect on cancer risk occurring mainly in males. Molecular characterization of human intestinal cell lines showed that the G-allele significantly correlated with increased basal expression of FoxO3A mRNA and protein.ConclusionOur results suggest an inverse correlation between the protective allele (G) copy number and cancer risk, and might be useful to optimize surveillance in HPS patients. Further investigations are needed to confirm our hypothesis and to ascertain whether differences in therapeutic response exist across genotypes.

FOXO3a from the Nucleus to the Mitochondria: A Round Trip in Cellular Stress Response

“…Importantly, previous reports failed to find an association between FOXO3 -coding variants and longevity [108]. Conversely, among non-coding genetic variants, the G-allele of the rs2802292 SNP, located in FOXO3 intron 2, has been reported to be strongly associated with longevity in different human populations [109,110]. A recent work showed that the 90-bp sequence around rs2802292 has an enhancer function.…”

FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs

“…In a recent study on patients with hamartomatous polyposis syndromes (HPS), an inverse correlation between the rs2802292 G-allele and cancer risk has been described. These syndromes are characterized by mutations in STK11 (Peutz-Jeghers syndrome, PJS) or PTEN (PTEN hamartoma tumor syndrome, PHTS) [71], which encode for FOXO3 upstream regulators [29]. Indeed, longevity-associated SNPs that do not act as protein-coding variants may reside in regulatory regions responsible for the activation of gene expression [72].…”

“…Indeed, longevity-associated SNPs that do not act as protein-coding variants may reside in regulatory regions responsible for the activation of gene expression [72]. For example, it was recently shown that the intronic rs2802292 G-allele is associated with increased FOXO3 basal expression [71,73] and that homozygosity for the G-allele correlates with lower frequency of age-related diseases in centenarians [35]. These data suggest that FOXO3 intron 2, and in particular the rs2802292 SNP, may act as a regulatory region.…”

“…However, according to a subgroup analysis carried out for each syndrome, the beneficial effect of the G-allele on cancer risk occurs mainly in HPS males. In particular, the proportion of PJS and PHTS males with cancer carrying an rs2802292 TT genotype was three times and seven times higher, respectively, than in PJS and PHTS males having at least one G-allele, while lower association effects were observed in female subjects [71]. The stronger association detected in male was hypothesized to be due to the fact that in men the protective effect is mostly dependent on the rs2802292 G-allele which, under stress conditions, promotes HSF1 recruitment to this region and higher FOXO3 expression [91], while in women it may be mainly due to estrogen-mediated ER activity on FOXO3 regulatory region, thus being less dependent on the presence of the rs2802292 G-allele (Fig.…”

Chasing the FOXO3: Insights into Its New Mitochondrial Lair in Colorectal Cancer Landscape

“…Numerous single nucleotide polymorphisms (SNPs) located in intronic regions of the gene have been shown to be associated with longevity in different human populations [56,57,58,59,60]. Notably, in humans the rs2802292 SNP G-allele at FOXO3a locus correlates with reduced frequency of age-related diseases in centenarians [61,62] and is associated with mortality risk reduction for coronary heart disease [63,64]. Moreover, it has been found to have enhancer functions, creating a binding site for HSF1 in response to stress stimuli [62].…”