Senescence biomarkers for cancer prevention in ulcerative colitis

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性结肠炎症性疾病，在美国影响了50万人，并使他们易患结直肠癌。目前预防癌症的方法是每1-3年进行一次终身内窥镜检查。结肠镜检查是昂贵的，耗时的，侵入性的，并不能总是检测到不典型增生。因此，需要更好的方法来检测发育不良和癌症的存在，并预测高危患者（估计为10%）。衰老生物标志物是有希望的候选者，因为它们在肿瘤前组织中被发现过表达，也因为衰老是由端粒缩短、氧化应激和DNA损伤诱导的，这三种刺激在溃疡性结肠炎的肿瘤发生中起作用。因此，我们假设UC患者的组织学正常组织中衰老可能会增加，这些患者共存或有发展为HGD或癌症的风险。本提案的主要目标是通过使用衰老生物标志物(1)准确区分UC进展者（高级别不典型增生或癌症患者）和UC非进展者，以及(2)预测内窥镜检查无发育不良的患者哪些具有高级别不典型增生或癌症的高风险，从而改善UC的结直肠癌预防。首先，我们将开发一组衰老标志物，可以通过免疫组织化学检测福尔马林固定石蜡包埋结肠组织。这是一项非常标准的技术，如果这些生物标志物在预防癌症方面的价值得到证实，将促进它们的临床应用。然后，我们将选择定义UC患者“进展者特征”的参数组合（标记物数量、表达水平、活检次数），我们将分析该特征区分UC进展者和非进展者的能力，首先在训练集中，然后在验证集中。最后，我们将通过大量前瞻性收集的溃疡性结肠炎患者队列，确定进展标志物和其他衰老生物标志物组合预测发展为发育不良或癌症风险的能力。相关性：溃疡性结肠炎是一种慢性结肠炎症性疾病，在美国影响了50万人，并使他们易患结直肠癌。该建议旨在通过使用在常规收集的结肠活检中容易测量的衰老生物标志物来改善这种疾病的癌症预防。这些标记将有助于预测哪些患者会患结直肠癌。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC), a chronic inflammatory disease of the colon, affects half a million individuals in the USA and predisposes them to develop colorectal cancer. The current method of cancer prevention consists on life-long endoscopic surveillance every 1-3 years. Colonoscopies are expensive, time consuming, invasive, and do not always detect dysplasia. Thus, better methods are needed to detect the presence of dysplasia and cancer and to predict the patients at risk (estimated to be 10%). Senescence biomarkers are promising candidates because they have been found overexpressed in pre-neoplastic tissues and also because senescence is induced by telomere shortening, oxidative stress and DNA damage, three stimuli that play a role in ulcerative colitis' tumorigenesis. Thus, we hypothesize that senescence is likely to be increased in histologically normal tissue from UC patients with coexistence or at risk of progression to HGD or cancer. The main goal of this proposal is to improve colorectal cancer prevention in UC by using senescence biomarkers to (1) accurately distinguish UC progressors (patients with high-grade dysplasia or cancer) from UC non progressors, and (2) predict which patients dysplasia-free at endoscopy are at high risk of developing high-grade dysplasia or cancer. First, we will develop a panel of senescence markers that can be detected by Immunohistochemistry in formalin-fixed paraffin embedded colon tissue. This is a very standard technique that will facilitate the clinical application of these biomarkers if their value in cancer prevention is proved. Then, we will select the combination of parameters (number of markers, level of expression, number of biopsies) that define the "progressor signature" for UC patients and we will analyze the ability of this signature to discriminate between UC progressors and non-progressors, first in a training set and then in a validation set. Finally, we will determine the ability of the progressor signature and additional combinations of senescence biomarkers to predict the risk of progression to dysplasia or cancer using a large, prospectively collected cohort of ulcerative colitis patients. RELEVANCE: Ulcerative colitis, a chronic inflammatory disease of the colon, affects half a million individuals in the USA and predisposes them to develop colorectal cancer. This proposal aims to improve cancer prevention in this disease by using senescence biomarkers easily measured in routinely collected colon biopsies. These markers will help to predict who are the patients that will develop colorectal cancer.