title: PIKing the type and pattern of PI3K pathway mutations in endometrioid endometrial carcinomas.
abstract: OBJECTIVE
  The vast majority of endometrioid endometrial carcinomas (EECs) harbor mutations in the PI3K pathway. Here we sought to determine whether the type and pattern of mutations targeting different components of the PI3K pathway are distinct between microsatellite stable (MSS) and high-level microsatellite instable (MSI-H) EECs.
  
  
  METHODS
  Whole exome massively parallel sequencing-based mutation data from EECs of The Cancer Genome Atlas (TCGA) were used to define the number, type and pattern of mutations affecting PI3K pathway-related genes, including AKT1, INPP4B, MTOR, PIK3CA, PIK3R1 and PTEN. EECs were classified as MSI-H (n=70) and MSS (n=109) based on seven MSI markers assessed by TCGA. Ultramutated cases were excluded.
  
  
  RESULTS
  Although the mutation rates and mutational signatures of MSS and MSI-H EECs were distinct, the prevalence of PI3K pathway mutations was similar between these two groups (all p>0.05), with the exception of PTEN mutations, which were more prevalent in MSI-H (61/70; 87%) than in MSS EECs (78/109; 72%; p=0.017). The PIK3CA hotspot mutations E542K, E545K, and H1047R were found to be significantly more prevalent in PIK3CA-mutant MSS (21/58, 36%) compared to PIK3CA-mutant MSI-H EECs (5/37, 13.5%; p=0.019).
  
  
  CONCLUSIONS
  Although the prevalence of mutations targeting PI3K pathway genes is similar between MSS and MSI-H EECs, PIK3CA hotspot mutations, which result in constitutive kinase activation, are significantly more prevalent in MSS than in MSI-H EECs. Our findings warrant further investigation of the role of different types of PIK3CA mutations and their predictive impact on distinct subtypes of EECs.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA; Department of Medical Sciences, University of Turin, via Santena 7, 10126 Turin, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchiò
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: De Filippo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, NY, USA. Electronic address: weigeltb@mskcc.org.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018269:Carcinoma, Endometrioid / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Endometrioid carcinoma; Hotspot; Microsatellite instability; Mutations; PI3K pathway