Pancreatic Cyst Fluid miRNOME for Biomarkers of Pancreatic Cancer

 描述(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年生存率为6%，因为大多数患者在确诊时存在局部或远处转移，而治疗选择极其有限。此外，粘液性囊性病变的浸润性癌的生物标志物有望解决尚未得到满足的关键临床需求，即可靠地区分惰性和侵袭性囊性病变，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。癌症快报2015；356：404-409)。此外，我们建议调查与PDAC相关的IPMN患者的cf-miR和血浆miR信号之间的重叠程度。这项研究将利用我的合作者金伯利·柯克伍德博士和帕梅拉·帕里斯博士分别在加州大学旧金山分校海伦·迪勒家族综合癌症中心进行的IPMN诊断和IPMN相关组织和生物标本库的内窥镜超声(EUS)诊断性囊样取样(请参阅所附信件)。我们提出了以下具体目标： 目的1：利用NGS和qRT-PCR建立用于IPMN风险分层的cf-miRNA生物标志物特征。 目的：探讨不同来源的cf-miRs在组织标本和表达非致瘤性人胰腺导管上皮细胞(HPDE)的突变型K-RasG12V细胞模型中的功能意义。 目的：评价胰腺囊肿患者血浆中cf-miRNA生物标志物的特征。

 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.