title: PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors.
abstract: Bladder tumors constitute a very heterogeneous disease. Superficial tumors are characterized by a high prevalence of FGFR3 mutations and chromosome 9 alterations. High-grade and muscle-invasive tumors are characterized by Tp53 mutations and aneuploidy. We have analyzed the sequence of exons 9 and 20 of PIK3CA in a panel of bladder tumors covering the whole spectrum of the disease. DNA from formalin-fixed, paraffin-embedded tumor sections was amplified by PCR and products were sequenced. In an unselected panel of tumors representative of the disease, the PIK3CA mutation prevalence was 13% (11 of 87). Mutations occurred mainly at the previously identified hotspots (codons 542, 545, 1007, and 1047). The distribution according to stage was as follows: papillary urothelial neoplasms of uncertain malignant potential (PUNLMP; 11 of 43, 25.6%), T(a) (9 of 57, 16%), T(1) (2 of 10, 20%), and muscle-invasive tumors (0 of 20, 0%; P = 0.019). Mutations were associated with low-grade tumors: grade 1 (6 of 27, 22.2%), grade 2 (3 of 23, 13%), and grade 3 (2 of 37, 5.4%; P = 0.047). Overall, PIK3CA mutations were strongly associated with FGFR3 mutations: 18 of 69 (26%) FGFR3(mut) tumors were PIK3CA(mut), versus 4 of 58 (6.9%) FGFR3(wt) tumors (P = 0.005). Our findings indicate that PIK3CA mutations are a common event that can occur early in bladder carcinogenesis and support the notion that papillary and muscle-invasive tumors arise through different molecular pathways. PIK3CA may constitute a novel diagnostic and prognostic tool, as well as a therapeutic target, in bladder cancer.
authors.affiliation: Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer del Dr. Aiguader 80, 08003 Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: López-Knowles
authors.forename: Silvia
authors.initials: S
authors.lastname: Hernández
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Adonina
authors.initials: A
authors.lastname: Tardón
authors.forename: Consol
authors.initials: C
authors.lastname: Serra
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
mesh_terms: D002291:Carcinoma, Papillary / Q000235:genetics*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D006801:Humans; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3