Characterization of the rs2802292 SNP identifies FOXO3A as a modifier locus predicting cancer risk in patients with PJS and PHTS hamartomatous polyposis syndromes

Giovanna Forte, Valentina Grossi, Valentina Celestini, Giuseppe Lucisano, Marco Scardapane, Dora Varvara, Margherita Patruno, Rosanna Bagnulo, Daria Loconte, Laura Giunti, Antonio Petracca, Sabrina Giglio, Maurizio Genuardi, Fabio Pellegrini, Nicoletta Resta, Cristiano Simone

Research output: Contribution to journalArticle

Abstract

Background: Hamartomatous 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. Methods: We typed rs2802292 in 150 HPS unrelated patients and characterized the expression of FoxO3A by quantitative PCR and immunoblot analysis in human intestinal cell lines. Results: We 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. Conclusion: Our 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.

Original languageEnglish
Article number661
JournalBMC Cancer
Volume14
Issue number1
Publication statusPublished - Sep 11 2014

Keywords

  • Cancer risk
  • FOXO3A
  • Hamartomatous polyposis syndromes
  • PHTS
  • PJS

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics
  • Medicine(all)

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    Forte, G., Grossi, V., Celestini, V., Lucisano, G., Scardapane, M., Varvara, D., Patruno, M., Bagnulo, R., Loconte, D., Giunti, L., Petracca, A., Giglio, S., Genuardi, M., Pellegrini, F., Resta, N., & Simone, C. (2014). Characterization of the rs2802292 SNP identifies FOXO3A as a modifier locus predicting cancer risk in patients with PJS and PHTS hamartomatous polyposis syndromes. BMC Cancer, 14(1), [661].