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PIK3CA Mutations Are an Early Genetic Alteration Associated with FGFR3 Mutations in Superficial Papillary Bladder Tumors

¹ Institut Municipal d'Investigació Mèdica; ² Universitat Pompeu Fabra; ³ Hospital del Mar, Barcelona, Spain; ⁴ Hospital General Universitario, Instituto Biología Molecular y Celular, Universidad Miguel Hernández, Elche, Spain; ⁵ Universidad de Oviedo, Oviedo, Spain; and ⁶ Consorci Hospitalari Parc Tauli, Sabadell, Spain

Requests for reprints: Francisco X. Real, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer del Dr. Aiguader 80, 08003 Barcelona, Spain. Phone: 34-93-2211009; Fax: 34-93-2213237; E-mail: preal{at}imim.es.

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%), T₁ (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. (Cancer Res 2006; 66(15): 7401-4)

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