Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway

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. Gene expression was studied in primary tumors from patients diagnosed with HNSCC

研究目的：磷脂酰肌醇3-激酶催化亚基α（PIK3CA）在多种人类肿瘤中频发发生改变，进而激活p110α的酶活性，促进不依赖生长因子的细胞增殖。PIK3CA的突变、基因扩增及过表达等改变在头颈部鳞状细胞癌（head and neck squamous cell carcinoma，HNSCC）中十分常见。本研究旨在探讨此类改变与临床结局的关联，以及其中涉及的分子机制。

材料与方法：本研究对来自癌症基因组图谱（The Cancer Genome Atlas，TCGA）队列（n=243）的原发性头颈部鳞状细胞癌肿瘤样本，开展了PIK3CA突变、拷贝数变异及全基因组表达谱分析。研究结果在来自拉科鲁尼亚大学医院（University Hospital of A Coruña，UHAC，n=62）的独立队列中得到验证。在来自12 de Octubre大学医院（University Hospital 12 de Octubre，UH12O，n=91）的队列中，本研究通过组织微阵列（tissue microarrays）检测了PIK3CA基因编码蛋白产物（PI3K p110α）的表达水平及核YAP（Yes-associated protein）的表达情况。

结果：仅PIK3CA基因的高表达与不良临床结局存在关联。基因表达、转录因子及蛋白特征分析提示，调控器官大小、干细胞维持及肿瘤发生的Hippo-YAP通路（Hippo-YAP pathway）的激活，可能是PIK3CA过表达肿瘤发生进展的潜在机制。组织微阵列实验结果显示，头颈部鳞状细胞癌肿瘤中PI3K p110α的表达水平与YAP的核定位呈正相关。

结论：头颈部鳞状细胞癌原发性肿瘤中PIK3CA的高表达，可用于识别复发风险较高的患者。此类肿瘤的进展可能依赖于Hippo-YAP通路，而非经典的Akt/mTOR通路（Akt/mTOR pathway）。这一发现可为患者的临床治疗方案选择提供重要参考。本研究针对确诊为头颈部鳞状细胞癌的患者的原发性肿瘤开展了基因表达分析。