Defining a novel subtype of luminal-TP53 mutant breast cancer with poor prognosis

 描述（由申请人提供）：我们将最近开发的综合聚类方法应用于癌症基因组图谱（TCGA）泛癌症数据集，并鉴定了一种新的管腔-TP 53乳腺癌亚型。管腔型乳腺癌通常表达雌激素受体（ER）和/或孕激素受体（PR），并且与低TP 53突变率（15-30%）相关，这是与不良预后相关的因素。令人惊讶的是，我们发现的管腔-TP 53亚型显示出显著更频繁的TP 53突变（>60%），并且显示出与基底样乳腺癌的分子特征非常相似的分子特征，其特征性地缺乏ER、PR和HER 2表达。反相蛋白质阵列数据分析显示，该亚型与其他乳腺癌亚型相比显示出更高水平的磷酸化AKT表达。鉴于通过PI 3 K-AKT信号通路的异常信号传导已被证明构成内分泌抵抗的机制，我们认为这些肿瘤不太可能对激素治疗有反应，但可能是包括PI 3 K/AKT/mTOR抑制的组合疗法的候选者。该提案旨在开发一种整合的基因组标签沿着临床方法，以高准确度对管腔-TP 53亚型进行分类，并在包括METABRIC队列和具有长期随访的回顾性MSKCC队列的独立数据集中验证该新型亚型。我们还将使用细胞系和患者来源的异种移植模型来研究腔-TP 53肿瘤中的分子驱动因子和治疗靶点。

 DESCRIPTION (provided by applicant): We applied a recently developed integrative clustering method to the Cancer Genome Atlas (TCGA) pan- cancer dataset and identified a novel luminal-TP53 breast cancer subtype. Luminal breast cancer typically expresses estrogen receptor (ER) and/or progesterone receptor (PR), and is associated with low TP53 mutation rate (15-30%) which is a factor linked with poor prognosis. Surprisingly, the luminal-TP53 subtype we discovered, showed substantially more frequent TP53 mutation (>60%), and displayed molecular features strongly resemble those of basal-like breast cancers, which characteristically lack ER, PR and HER2 expression. Reverse-phase protein array data analysis revealed that this subtype displayed higher level of phospho-AKT expression as compared to other breast cancer subtypes. Given that aberrant signaling through the PI3K-AKT signaling pathway has been shown to constitute a mechanism of endocrine resistance, we posit that these tumors are unlikely to respond to hormone therapy but are possible candidates for combinatorial therapies including PI3K/AKT/mTOR inhibition. This proposal aims to develop an integrated genomic signature along with clinical methods to classify the luminal-TP53 subtype with high accuracy, and to validate this novel subtype in independent datasets including the METABRIC cohort and a retrospective MSKCC cohort with long- term follow-up. We will also use cell line and patient-derived xenograft models to study the molecular drivers and therapeutic targets in luminal-TP53 tumors.