The major underlying gene defect(s) of FPC has not yet been identified, but causative BRCA2, PALB2, CDKN2a, and ATM germline mutations were identified in about 10% to 15% of the FPC families [4], [5], [6], [7], [8] and [9]. It has been

recommended by a recent consensus conference that individuals at risk (IAR) of FPC families should undergo PC screening under research protocol conditions  [3]. Individuals with at least a 5- to 10-fold BGB324 increased risk of PC, such as members of FPC families with two or more affected first-degree relatives, are considered to be candidates for screening. Most experts currently consider magnetic resonance imaging (MRI) and endoscopic ultrasonography to be the best imaging modalities for FPC screening [4]. Unfortunately, these imaging tools are not able to reliably visualize early PC or, even more important, its high-grade precursor lesions, i.e., pancreatic intraepithelial neoplasia grade 3 (PanIN3). Thus, there is a definite need for biomarkers to facilitate BMN 673 mouse screening of IAR in the setting of FPC to identify those individuals with high-grade PanINs before the development of invasive carcinoma that could allow for a curative resection. Familial as well as sporadic PCs are characterized by a progression from low-grade

PanINs (PanIN1) over carcinoma in situ (PanIN3) to invasive cancer. The majority of pancreatic specimens of resected FPC individuals reveal multifocal PanIN disease in addition to small intraductal papillary mucinous neoplasms (IPMNs)

of branch duct/gastric type [10], [11], [12] and [13]. Branch-duct IPMNs might find more be a surrogate marker for the presence of high-grade PanIN lesions in other locations of the gland in the FPC setting [14]. The stepwise progression from PanIN to invasive PC comprises activating mutations of the Kras oncogene and inactivation of the ARF-p53 tumor suppressor pathway in the great majority of cases  [15]. Nowadays, genetically engineered mouse models of PC that closely recapitulate the histopathogenesis and progression of the human disease are available. These include the LSL-KrasG12D/+;Pdx1-Cre (KC) mice that progress up to PanIN3 lesions and the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx1-Cre (KPC) mice that develop PanIN lesions and ultimately invasive carcinoma at 5 to 10 months [16], [17] and [18]. These mouse models are considered an adequate tool for the study of biomarkers [16] and [17], especially given the lack of FPC patients with preoperative, well-defined high-grade PanIN lesions. MicroRNAs (miRNAs) are small non-coding molecules, which have an important function in regulating RNA stability and gene expression. The deregulation of miRNAs has been linked to cancer development and tumor progression [19].