Ramón García-Escudero1, Carmen Segrelles2, Marta Dueñas2, María Pombo3, Claudio Ballestín4, Marina Alonso-Riaño4, Pablo Nenclares5, Roberto Álvarez-Rodríguez6, Gregorio Sánchez-Aniceto7, Ana Ruíz-Alonso5, José Luis López-Cedrún3, Jesús M Paramio2, Corina Lorz8. 1. Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain; Molecular Oncology, University Hospital 12 de Octubre, Research Institute, 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain; Institute of Oncology Research (IOR), and Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland. Electronic address: ramon.garcia@ciemat.es. 2. Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain; Molecular Oncology, University Hospital 12 de Octubre, Research Institute, 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. 3. Department of Maxillofacial Surgery, University Hospital of A Coruña, As Xubias, 84, 15006 A Coruña, Spain. 4. Department of Pathology, University Hospital 12 de Octubre, Ave Córdoba s/n, 28041 Madrid, Spain. 5. Department of Radiation Oncology, University Hospital 12 de Octubre, Ave Córdoba s/n, 28041 Madrid, Spain. 6. Department of Pathology, University Hospital of A Coruña, As Xubias, 84, 15006 A Coruña, Spain. 7. Department of Maxillofacial Surgery, University Hospital 12 de Octubre, Ave Córdoba s/n, 28041 Madrid, Spain. 8. Molecular Oncology Unit, CIEMAT (ed 70A), Ave Complutense 40, 28040 Madrid, Spain; Molecular Oncology, University Hospital 12 de Octubre, Research Institute, 12 de Octubre i+12, Ave Córdoba s/n, 28041 Madrid, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain. Electronic address: clorz@ciemat.es.
Abstract
OBJECTIVES: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many human tumors, leading to the activation of p110α enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved. MATERIAL AND METHODS: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n = 243). The results were validated in an independent cohort form the University Hospital of A Coruña (UHAC, n = 62). Expression of the PIK3CA gene protein product (PI3K p110α) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n = 91). RESULTS: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110α levels correlated with YAP nuclear localization in HNSCC tumors. CONCLUSIONS: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients.
OBJECTIVES: Phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) is commonly altered in many humantumors, leading to the activation of p110α enzymatic activity that stimulates growth factor-independent cell growth. PIK3CA alterations such as mutation, gene amplification and overexpression are common in head and neck squamous cell carcinoma (HNSCC) and. We aim to explore how these alterations and clinical outcome are associated, as well as the molecular mechanisms involved. MATERIAL AND METHODS: Mutation and copy-number variation in PIK3CA, and whole-genome expression profiles, were analyzed in primary HNSCC tumors from The Cancer Genome Atlas (TCGA) cohort (n = 243). The results were validated in an independent cohort form the University Hospital of A Coruña (UHAC, n = 62). Expression of the PIK3CA gene protein product (PI3K p110α) and nuclear YAP were assessed in tissue microarrays in a cohort from the University Hospital 12 de Octubre (UH12O, n = 91). RESULTS: Only high expression of the PIK3CA gene was associated with poor clinical outcome. The study of gene expression, transcription factor and protein signatures suggested that the activation of the Hippo-YAP pathway, involved in organ size, stem cell maintenance and tumorigenesis, could underlie tumor progression in PI3KCA overexpressing tumors. Tissue arrays showed that PI3K p110α levels correlated with YAP nuclear localization in HNSCC tumors. CONCLUSIONS: High expression of PIK3CA in HNSCC primary tumors identifies patients at high risk for recurrence. In these tumors, progression could rely on the Hippo-YAP pathway instead of the canonical Akt/mTOR pathway. This observation could have important implications in the therapeutic options for patients.
Authors: Sisi Li; Xiao-Ting Huang; Meng-Yao Wang; Dong-Ping Chen; Ming-Yi Li; Yan-Yi Zhu; Yi Yu; Lu Zheng; Bin Qi; Jin-Quan Liu Journal: Front Oncol Date: 2021-06-24 Impact factor: 6.244