Germline PTEN Promoter Mutations and Deletions in Cowden/Bannayan-Riley-Ruvalcaba Syndrome Result in Aberrant PTEN Protein and Dysregulation of the Phosphoinositol-3-Kinase/Akt Pathway

摘要: Germline intragenic mutations in PTEN are associated with 80% of patients Cowden syndrome (CS) and 60% Bannayan-Riley-Ruvalcaba (BRRS). The underlying genetic causes remain to be determined a considerable proportion classic CS BRRS without polymerase chain reaction (PCR)-detectable mutation. We hypothesized that gross gene deletions the promoter might alternatively account for subset apparently mutation-negative BRRS. Using real time multiplex PCR techniques, we identified three germline hemizygous 122 (N=95) or (N=27). Fine mapping suggested one deletion encompassed whole other two included exon 1 exons 1–5 PTEN, respectively. Two were diagnosed BRRS, patient was BRRS/CS overlap (features both). Thus 3 (11%) 27 BRRS/CS-overlap had deletions. Analysis revealed nine cases (7.4%) harboring heterozygous mutations. All CS, representing almost 10% all subjects CS. Eight breast cancers and/or benign tumors but, otherwise, oligo-organ involvement. protein analysis, from deletion-positive five PTEN-promoter-mutation–positive samples, 50% reduction multiple bands immunoreactive protein, In contrast, control samples showed only expected band. Further, an elevated level phosphorylated Akt detected promoter-mutation–positive compared controls, indicating absence marked functional PTEN. These data suggest PCR-detected offered clinical analysis promoter-mutation