title: Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas.
abstract: OBJECTIVE
  In breast cancer, the PIK3CA gene is frequently mutated at "hotspots" in exons 9 and 20, corresponding to the helical and kinase domains, respectively. We decided to investigate the association of PIK3CA mutations with pathologic features and clinical outcome in a large series of patients with breast cancer.
  
  
  METHODS
  Frozen samples from 163 consecutive patients were analyzed for PIK3CA mutations using PCR single-strand conformation polymorphism and sequence analyses.
  
  
  RESULTS
  We identified 46 missense mutations, 24 (53%) in exon 9, and 21 (47%) in exon 20. Twelve (50%) of the 24 mutations in exon 9 were of the E542K type and 11 (46%) were of the E545K type. Twenty (95%) of the 21 mutations in exon 20 were H1047R substitutions. Mutations in exon 9 were more frequent in lobular carcinomas (42% of cases) than in ductal carcinoma (11% of cases; P = 0.002). At univariate survival analysis, PIK3CA exon 20 mutations were associated with prolonged overall and disease-free survival, whereas mutations in exon 9 were associated with significantly worse prognosis. At multivariate analysis, exon 9 PIK3CA mutations were the strongest independent factor to predict poor prognosis for disease-free survival (P = 0.0003) and overall survival (P = 0.001).
  
  
  CONCLUSIONS
  Our data show that exon 9 PIK3CA mutations are typical of infiltrating lobular carcinomas. In addition, they indicate that PIK3CA mutations in different exons are of different prognostic value: exon 9 mutations are independently associated with early recurrence and death, whereas exon 20 PIK3CA mutations are associated with optimal prognosis.
authors.affiliation: Unit of Surgical Pathology, Laboratory of Molecular Pathology S. Chiara Hospital, Trento, Italy, and Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chieti, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Barbareschi
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cotrupi
authors.forename: Fabio
authors.initials: F
authors.lastname: Barassi
authors.forename: Maela
authors.initials: M
authors.lastname: Del Grammastro
authors.forename: Antonella
authors.initials: A
authors.lastname: Ferro
authors.forename: Paolo
authors.initials: P
authors.lastname: Dalla Palma
authors.forename: Enzo
authors.initials: E
authors.lastname: Galligioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D058534:Class I Phosphatidylinositol 3-Kinases; D005091:Exons; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis* / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D011379:Prognosis; D017434:Protein Structure, Tertiary; D016896:Treatment Outcome
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human