Senescence biomarkers for cancer prevention in ulcerative colitis

见说明）： 溃疡性结肠炎（UC）是一种慢性结肠炎性疾病，影响着世界上50万人， 美国和易患结直肠癌。目前预防癌症的方法包括 每1-3年进行一次终身内窥镜监测。结肠镜检查既昂贵又耗时， 侵入性，并不总是检测发育不良。因此，需要更好的方法来检测 异型增生和癌症，并预测患者的风险（估计为10%）。衰老生物标志物是 有希望的候选物，因为已经发现它们在肿瘤前组织中过表达， 由于衰老是由端粒缩短、氧化应激和DNA损伤引起的， 在溃疡性结肠炎的肿瘤发生中起作用。因此，我们假设衰老很可能是 来自共存或有进展为HGD风险的UC患者的组织学正常组织增加 或者癌症该提案的主要目标是通过使用以下方法改善UC中的结直肠癌预防 衰老生物标志物，以（1）准确区分UC进展者（高度异型增生或 癌症），以及（2）预测哪些患者在内镜检查时无异型增生处于高风险中 高度发育不良或癌症的风险首先，我们将开发一组衰老标记物， 在福尔马林固定的石蜡包埋的结肠组织中通过免疫组化检测。这是一个非常 如果这些生物标志物在癌症中的价值， 预防已经证明。然后，我们将选择参数的组合（标记物的数量， 表达，活检次数），定义了UC患者的“进展标志”，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，我们将确定进步者签名的能力和额外的 使用衰老生物标志物的组合来预测进展为发育异常或癌症的风险， 前瞻性收集的溃疡性结肠炎患者的大型队列。 相关性（参见说明）： 溃疡性结肠炎是一种慢性结肠炎性疾病，在美国有50万人患病 并使他们更容易患上结肠直肠癌。该提案旨在改善这一领域的癌症预防工作。 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治疗疾病。这些 标记物将有助于预测谁是将发展为结直肠癌的患者。

See instoictions): Ulcerative colitis (UC), a chronic inflammatory disease ofthe 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 coexistance 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 facilite 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 beween 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 (See instructions): Ulcerative colitis, a chronic inflammatory disease ofthe 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.