title: PIK3CA gene alterations in bladder cancer are frequent and associate with reduced recurrence in non-muscle invasive tumors.
abstract: Bladder cancer (BC) is the fifth most common cancer in the world, being the non-muscle invasive tumors (NMIBC) the most frequent. NMIBC shows a very high frequency of recurrence and, in certain cases, tumor progression. The phosphatidylinositol 3-kinase (PI3K) pathway, which controls cell growth, tumorigenesis, cell invasion and drug response, is frequently activated in numerous human cancers, including BC, in part through alterations of PIK3CA gene. However, the significance of PIK3CA gene alterations with respect to clinicopathological characteristics, and in particular tumor recurrence and progression, remains elusive. Here, we analyzed the presence of mutations in FGFR3 and PIK3CA genes and copy number alterations of PIK3CA gene in bladder tumor and their correspondent paired normal samples from 87 patients. We observed an extremely high frequency of PIK3CA gene alterations (mutations, copy gains, or both) in tumor samples, affecting primarily T1 and T2 tumors. A significant number of normal tissues also showed mutations and copy gains, being coincident with those found in the corresponding tumor sample. In low-grade tumors PIK3CA mutations associated with FGFR3 mutations. Alterations in PIK3CA gene resulted in increased Akt activity in tumors. Interestingly, the presence of PIK3CA gene alterations, and in particular gene mutations, is significantly associated with reduced recurrence of NMIBC patients. Importantly, the presence of FGFR3 mutations may influence the clinical outcome of patients bearing alterations in PIK3CA gene, and increased recurrence was associated to FGFR3 mutated, PIK3CA wt tumors. These findings may have high relevance in terms of using PI3K-targeted therapies for BC treatment.
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Dueñas
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Escudero
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Villacampa
authors.affiliation: Epithelial Carcinogenesis Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO) Melchor Fernández Almagro, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Marqués
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Saiz-Ladera
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Duarte
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Martínez
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: M José
authors.initials: MJ
authors.lastname: Gómez
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Martín
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Manoli
authors.initials: M
authors.lastname: Fernández
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Epithelial Carcinogenesis Group, Molecular Pathology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO) Melchor Fernández Almagro, Madrid, Spain.|Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Servicio de Anatomía Patológica, Centro de Investigación Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Rodriguez-Peralto
authors.affiliation: Unidad de Uro-Oncología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: De La Rosa
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D018628:Gene Dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D015398:Signal Transduction; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
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; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; FGFR3; PI3K pathway; PIK3CA; bladder cancer; p110α; recurrence