Pancreatic Cyst Fluid miRNOME for Biomarkers of Pancreatic Cancer

用于胰腺癌生物标志物的胰腺囊肿液 miRNOME

• 批准号: 9025239
• 负责人: Subrata Sen
• 金额: $ 22.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9025239
• 关键词: Abdomen; Address; Adenocarcinoma; Benign; Biological Markers; Cell Line; Clinical; Clinical Management; Cohort Studies; Comprehensive Cancer Center; Cyst; Cyst Fluid; Cystic Lesion; Cystic Neoplasm; Development; Diagnosis; Diagnostic; Disease; Distal; Ductal Epithelial Cell; Dysplasia; Excision; Family; General Population; Histopathology; Human; Image; Imaging Techniques; In Situ Hybridization; In Vitro; Incidence; Indolent; Lesion; Letters; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; MicroRNAs; Modeling; Morbidity - disease rate; Mucinous; Mucinous Neoplasm; Mucins; Mutation; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Cyst; Pancreatic Ductal Adenocarcinoma; Papillary; Paris, France; Pathway interactions; Patients; Perioperative; Phase; Plasma; Protein Array Analysis; Publishing; Reporting; Resected; Risk; Sample Size; Sampling; Scanning; Sequence Analysis; Serous Cystadenoma; Specimen; Stratification; Survival Rate; Symptoms; Time; Tissue Sample; Tissues; Transfection; Ultrasonography; United States; University of Texas M D Anderson Cancer Center; Validation; X-Ray Computed Tomography; candidate marker; circulating microRNA; cohort; curative treatments; differential expression; early detection biomarkers; high risk; locked nucleic acid; microRNA biomarkers; mortality; mutant; next generation sequencing; novel; patient population; public health relevance; tumorigenic

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with an average 5 year survival rate of <6%, since most patients present with local or distal metastasis at the time of diagnosis when curative treatment options are extremely limited. Asymptomatic pancreatic cysts detected in more than 2% of the general patient population with abdominal imaging presents a unique opportunity for developing early detection biomarkers of PDAC since mucin-secreting pancreatic cysts, such as the more frequently detected intraductal papillary mucinous neoplasms (IPMNs) and the less frequent mucinous cystic neoplasms (MCNs) are bona fide precursor lesions of PDAC. Furthermore, biomarkers of invasive cancer from mucinous cystic lesions is expected to address the critical unmet clinical need of reliably distinguishing indolent from aggressive cystic lesions to help patients with indolent disease avoid the risk of surgery associated morbidity and mortality. In a recent limited sample size cohort study, we identified by NextGen sequencing (NGS) differentially abundant cyst fluid miRs (cf-miR) from patients with high grade IPMN-invasive pancreatic cancer compared with those with low grade IPMN demonstrating the feasibility of developing cf-miR signatures as early detection biomarkers for stratifying high risk IPMN predisposed to progress to invasive PDAC from low risk indolent cysts (Wang et al. Cancer Letters 2015; 356: 404-409). In this project, we are proposing to undertake detailed analyses of NGS derived cyst fluid miRNome (cf-miR) from IPMN patients with benign or low grade dysplasia and those with high grade dysplasia- invasive cancer to develop cf-miR signature that can differentiate aggressive IPMN from benign and indolent lesions. Additionally, we propose to investigate extent of overlap between the cf-miR and the plasma miR signatures from IPMN patients associated with PDAC. The study will take advantage of diagnostic cystic sampling with endoscopic ultrasound (EUS) for IPMN diagnosis and IPMN related histological tissue and bio-specimen banking at the Helen Diller Family Comprehensive Cancer Center at UCSF by my collaborators, Dr. Kimberly Kirkwood and Dr. Pamela Paris respectively (Please see the letters attached). We propose the following specific aims: Aim 1: Develop cf-miRNA biomarker signature for IPMN risk stratification utilizing NGS and qRT-PCR. Aim 2: Investigate functional significance of the differentially abundant cf-miRs in resected tissue samples and in an in vitro cell line model of mutant K-RasG12V expressing non-tumorigenic human pancreatic ductal epithelial (HPDE) cells. Aim 3: Evaluate cf-miRNA biomarker signatures in blood plasma from patients with pancreatic cysts.

 描述（由申请人提供）：胰腺导管腺癌 (PDAC) 是一种高度致命的癌症，平均 5 年生存率 <6%，因为大多数患者在诊断时就出现局部或远端转移，而治疗选择极其有限。通过腹部影像在超过 2% 的普通患者群体中检测到无症状胰腺囊肿，为开发 PDAC 早期检测生物标志物提供了独特的机会，因为分泌粘蛋白的胰腺囊肿，例如更频繁检测到的导管内乳头状粘液性肿瘤 (IPMN) 和不太常见的粘液性囊性肿瘤 (MCN) PDAC 的真实前体病变。此外，来自粘液性囊性病变的侵袭性癌症的生物标志物有望解决可靠区分惰性和侵袭性囊性病变的关键未满足的临床需求，以帮助惰性疾病患者避免手术相关的发病率和死亡率的风险。在最近的一项有限样本量队列研究中，我们通过 NextGen 测序 (NGS) 发现，与低级别 IPMN 患者相比，高级别 IPMN 侵袭性胰腺癌患者的囊液 miR (cf-miR) 丰度存在差异，证明了开发 cf-miR 特征作为早期检测生物标志物，用于对易从低风险进展为侵袭性 PDAC 的高风险 IPMN 进行分层的可行性 惰性囊肿（Wang 等人 Cancer Letters 2015；356：404-409）。在这个项目中，我们建议对良性或低度不典型增生 IPMN 患者以及高度不典型增生浸润性癌症患者的 NGS 衍生囊液 miRNome (cf-miR) 进行详细分析，以开发 cf-miR 特征，以区分侵袭性 IPMN 与良性和惰性病变。此外，我们建议研究与 PDAC 相关的 IPMN 患者的 cf-miR 和血浆 miR 特征之间的重叠程度。该研究将利用我的合作者 Kimberly Kirkwood 博士和 Pamela Paris 博士分别在加州大学旧金山分校海伦迪勒家庭综合癌症中心进行的 IPMN 诊断和 IPMN 相关组织学组织和生物样本库的诊断性囊性取样和内镜超声 (EUS) 的优势（请参阅所附信件）。我们提出以下具体目标： 目标 1：利用 NGS 和 qRT-PCR 开发用于 IPMN 风险分层的 cf-miRNA 生物标志物特征。 目标 2：研究切除组织样本和表达非致瘤性人胰腺导管上皮 (HPDE) 细胞的突变 K-RasG12V 的体外细胞系模型中差异丰富的 cf-miR 的功能意义。 目标 3：评估胰腺囊肿患者血浆中的 cf-miRNA 生物标志物特征。