Simplified Diagnosis of a Prognostic Wound Response Signature in Breast Cancer

描述（由申请人提供）：人体具有巨大的愈合能力，但细胞生长、组织再生和招募新血管的能力也可能在癌症进展过程中被滥用。在许多常见的癌症中，尤其是乳腺癌，肿瘤表达一组512个基因的能力通常在伤口反应模型中看到，这是随后转移和死亡的一个强大而准确的预测指标。512基因“伤口特征”的预后信息是独立的，比传统的临床和病理危险因素更具信息性。伤口特征也独立于先前确定的预后特征和分子标记。然而，由于涉及的基因数量众多，使得伤口特征在日常临床实践中难以实现。该提案的中心目标是开发能够大大简化伤口特征诊断的技术。为此，我们建议开发两种技术。首先，我们将开发一种基于检测其两个调节基因的DNA扩增来诊断伤口特征的方法。我们最近发现伤口特征是两个关键生长调节基因扩增的结果，这预示着测量调节基因将足以诊断伤口特征并预测患者预后。其次，我们将开发一种新的基因选择算法和RNA扩增技术，通过测量肿瘤样本中一小部分基因转录物来重现伤口特征的预后能力。在资助期结束时，我们设想通过标准的福尔马林固定石蜡包埋肿瘤切片诊断伤口特征的能力。

DESCRIPTION (provided by applicant): The human body has a tremendous capacity for healing, but the ability of cells to grow, regenerate tissues, and recruit new blood vessels may also be misused during cancer progression. In many common cancers, especially breast cancer, the ability of tumors to express a set of 512 genes seen normally in a model of wound response is a powerful and accurate predictor of subsequent metastasis and death. The prognostic information of the 512 gene "wound signature" was independent of and more informative than traditional clinical and pathologic risk factors. The wound signature was also independent of previously identified prognostic signatures and molecular markers. However, the large number of genes involved renders the wound signature difficult to implement in daily clinical practice. The central goal of this proposal is to develop technologies that will greatly simplify the diagnosis of the wound signature. We propose to develop two technologies toward this end. First, we will develop a method to diagnose the wound signature based on detecting DNA amplification of its two regulator genes. Our recent discovery that the wound signature is a consequence of amplification of two key growth regulator genes predicts that measuring the regulator genes will be sufficient to diagnose the wound signature and to prognosticate patient outcome. Second, we will develop a novel gene picking algorithm and RNA amplification technology that can reproduce the prognostic power of the wound signature by measuring only a small fraction of gene transcripts from tumor samples. At the end of the funding period, we envision the capacity to diagnose the wound signature from standard formalin-fixed, paraffin embedded tumor sections. Breast cancer is the second most common cause of cancer death for women in the United States. These deaths are most often caused by the spread of breast cancer to other sites of the body, a process that involves genes normally reserved for wound healing. Improved technology to identify the wound response genes in breast cancer will improve the risk assessment of breast cancer patients and better guide patients to appropriate therapies.