title: Molecular profiling of infiltrating urothelial carcinoma of bladder and nonbladder origin.
abstract: BACKGROUND
  Infiltrating UC represents the second most common genitourinary malignancy. Advanced UC has a poor prognosis and new treatments are needed. Molecular profiling of UC might identify biomarkers associated with targeted therapies or chemotherapeutics, providing physicians with new treatment options.
  
  
  METHODS
  Five hundred thirty-seven cases of locally advanced or metastatic UC of the bladder, 74 nonbladder, and 55 nonurothelial bladder cancers were profiled using mutation analysis, in situ hybridization, and immunohistochemistry assays for biomarkers predictive of therapy response.
  
  
  RESULTS
  Molecular profiling of UC showed high overexpression of topoisomerase 2α, common phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha and/or phosophatase and tensin homolog (PTEN) alterations in nonbladder (27%) and bladder UC (21%), and rare gene mutations across subtypes. Compared with nonbladder, bladder UC consistently exhibited more frequent abnormal protein expression, including HER2 (10% vs. 3%; P = .04), tyrosine protein c-Kit receptor kinases (11% vs. 5%), c-Met proto-oncogene, receptor tyrosine kinases (25% vs. 8%), androgen receptor (16% vs. 6%), O(6)-methylguanine-methyltransferase (63% vs. 43%), ribonucleotide reductase M1 (32% vs. 11%), Serum protein acidic and rich in cysteine (SPARC) (69% vs. 33%), and topoisomerase 1 (63% vs. 39%). Bladder UC also exhibited increased amplification of HER2 (12% vs. 2%; P = .06).
  
  
  CONCLUSIONS
  Comprehensive molecular profiling of UC identified a large number of biomarkers aberrations that might direct treatment in conventional chemotherapies and targeted therapies, not currently recommended in this population. As a group, bladder UC exhibited higher levels of actionable biomarkers, suggesting that UC from different primary sites and non-UC are driven by different molecular pathways. These differences could have clinical implications resulting in different treatment regimens depending on the site of origin of UC.
authors.affiliation: Caris Life Sciences, Phoenix, AZ. Electronic address: smillis@carisls.com.
authors.forename: Sherri Z
authors.initials: SZ
authors.lastname: Millis
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: David
authors.initials: D
authors.lastname: Bryant
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Gargi
authors.initials: G
authors.lastname: Basu
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Ryan
authors.initials: R
authors.lastname: Bender
authors.affiliation: Department of Pathology, Clinical Center, University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
authors.forename: Semir
authors.initials: S
authors.lastname: Vranic
authors.affiliation: Caris Life Sciences, Phoenix, AZ.
authors.forename: Zoran
authors.initials: Z
authors.lastname: Gatalica
authors.affiliation: US Oncology Research Comprehensive Cancer Centers of Nevada, Las Vegas, NV.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005784:Gene Amplification; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000090063:Proto-Oncogene Mas; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D014565:Urogenital Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas
keywords: Personalized medicine; Targeted therapy; Urinary bladder; Urinary tract; Urothelial carcinoma