title: Characterization of the rs2802292 SNP identifies FOXO3A as a modifier locus predicting cancer risk in patients with PJS and PHTS hamartomatous polyposis syndromes.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Forte
authors.forename: Valentina
authors.initials: V
authors.lastname: Grossi
authors.forename: Valentina
authors.initials: V
authors.lastname: Celestini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lucisano
authors.forename: Marco
authors.initials: M
authors.lastname: Scardapane
authors.forename: Dora
authors.initials: D
authors.lastname: Varvara
authors.forename: Margherita
authors.initials: M
authors.lastname: Patruno
authors.forename: Rosanna
authors.initials: R
authors.lastname: Bagnulo
authors.forename: Daria
authors.initials: D
authors.lastname: Loconte
authors.forename: Laura
authors.initials: L
authors.lastname: Giunti
authors.forename: Antonio
authors.initials: A
authors.lastname: Petracca
authors.forename: Sabrina
authors.initials: S
authors.lastname: Giglio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Genuardi
authors.forename: Fabio
authors.initials: F
authors.lastname: Pellegrini
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.affiliation: Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), Università di Bari "Aldo Moro", Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. cristianosimone73@gmail.com.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006147:Guanine / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010580:Peutz-Jeghers Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006147:Guanine