Poor prognosis in cancer is associated with a expression signature of aberrant PTEN tumor suppressor pathway activity. Homo sapiens

Pathway-specific therapy is the future of cancer management. The oncogenic phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated in solid tumors; however, currently, no reliable test for PI3K pathway activation exists for human tumors. Taking advantage of the observation that loss of PTEN, the negative regulator of PI3K, results in robust activation of this pathway, we developed and validated a microarray gene expression signature for immunohistochemistry (IHC)-detectable PTEN loss in breast cancer (BC). The most significant signature gene was PTEN itself, indicating that PTEN mRNA levels are the primary determinant of PTEN protein levels in BC. Some PTEN IHC-positive BCs exhibited the signature of PTEN loss, which was associated to moderately reduced PTEN mRNA levels cooperating with specific types of PIK3CA mutations and/or amplification of HER2. This demonstrates that the signature is more sensitive than PTEN IHC for identifying tumors with pathway activation. In independent data sets of breast, prostate, and bladder carcinoma, prediction of pathway activity by the signature correlated significantly to poor patient outcome. Stathmin, encoded by the signature gene STMN1, was an accurate IHC marker of the signature and had prognostic significance in BC. Stathmin was also pathway-pharmacodynamic in vitro and in vivo. Thus, the signature or its components such as stathmin may be clinically useful tests for stratification of patients for anti-PI3K pathway therapy and monitoring therapeutic efficacy. This study indicates that aberrant PI3K pathway signaling is strongly associated with metastasis and poor survival across carcinoma types, highlighting the enormous potential impact on patient survival that pathway inhibition could achieve. Keywords: Disease state analysis Overall design: 105 breast cancer tumor samples were analyzed on 2-color cDNA microarrays using the Stratagene Universal Human Reference RNA as the common reference sample.

通路靶向治疗是癌症管理的未来发展方向。致癌性磷脂酰肌醇3-激酶（phosphatidylinositol 3-kinase, PI3K）通路在实体瘤中常发生激活，但目前尚无针对人类肿瘤的可靠PI3K通路激活检测手段。本研究基于PI3K的负调控因子PTEN缺失可显著激活该通路这一发现，开发并验证了一种可用于检测乳腺癌（breast cancer, BC）中免疫组化（immunohistochemistry, IHC）可识别的PTEN缺失的微阵列基因表达特征。该特征最具显著性的基因为PTEN本身，这表明在乳腺癌中，PTEN信使RNA（messenger RNA, mRNA）水平是PTEN蛋白水平的主要决定因素。部分PTEN免疫组化阳性的乳腺癌样本呈现PTEN缺失特征，该特征与PTEN mRNA水平中度降低、特定类型的PIK3CA突变以及（或）HER2扩增存在协同关联。这表明该特征在识别存在通路激活的肿瘤时，灵敏度优于PTEN免疫组化检测。在乳腺癌、前列腺癌与膀胱癌的独立数据集分析中，通过该特征预测的通路活性与患者不良预后显著相关。由特征基因STMN1编码的丝切蛋白（Stathmin）是该特征的精准免疫组化标志物，且在乳腺癌中具有预后评估价值。丝切蛋白在体外与体内实验中同样可作为通路药效动力学标志物。因此，该特征或其组分（如丝切蛋白）可作为临床实用检测手段，用于抗PI3K通路治疗的患者分层以及治疗疗效的动态监测。本研究表明，在各类癌种中，异常激活的PI3K通路信号转导与肿瘤转移及患者不良生存结局显著相关，这凸显了通路抑制疗法对改善患者生存结局的巨大潜在价值。
关键词：疾病状态分析
整体实验设计：本研究采用Stratagene公司的通用人类参考RNA作为共同对照样本，在双色互补DNA（complementary DNA, cDNA）微阵列上对105例乳腺癌肿瘤样本进行了分析。