title: Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors.
abstract: BACKGROUND
  An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS) in patients with advanced urothelial carcinoma (UC) treated with platinum-based chemotherapy.
  
  
  METHODS
  DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE) invasive high-grade UC samples and were screened for mutations, copy number variation (CNV) and gene expression analysis. Clinical data were available from 85 cases. Mutations were analyzed by mass-spectrometry based on genotyping platform (Oncomap 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio ≥0.4, or ≤0.6 were defined as either having copy number gain or loss and significantly recurrent CNV across the set of samples were determined using a GISTIC analysis. Expression analysis on selected relevant UC genes was conducted using Nanostring. To define the co-occurrence pattern of mutations and CNV, we grouped genomic events into 5 core signal transduction pathways: 1) TP53 pathway, 2) RTK/RAS/RAF pathway, 3) PI3K/AKT/mTOR pathway, 4) WNT/CTNNB1, 5) RB1 pathway. Cox regression was used to assess pathways abnormalities with survival outcomes.
  
  
  RESULTS
  35 samples (41%) harbored mutations on at least one gene: TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). 66% of patients had some sort of CNV. PIK3CA/AKT/mTOR pathway alteration (mutations+CNV) had the greatest impact on OS (p=0.055). At a gene level, overexpression of CTNNB1 (p=0.0008) and PIK3CA (p=0.02) were associated with shorter OS. Mutational status on PIK3CA was not associated with survival. Among other individually found genomic alterations, TP53 mutations (p=0.07), mTOR gain (p=0.07) and PTEN overexpression (p=0.08) have a marginally significant negative impact on OS.
  
  
  CONCLUSIONS
  Our study suggests that targeted therapies focusing on the PIK3CA/AKT/mTOR pathway genomic alterations can generate the greatest impact in the overall patient population of high-grade advanced UC.
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Biostatistics and Computational Biology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States of America.
authors.forename: Lillian
authors.initials: L
authors.lastname: Werner
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Leow
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Mullane
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: André P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Biostatistics and Computational Biology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, United States of America.
authors.forename: Markus
authors.initials: M
authors.lastname: Riester
authors.affiliation: Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States of America.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Van Allen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Rosenberg
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010984:Platinum / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014571:Urologic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D010984:Platinum; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human