Pancreatic cancer is the fourth leading cause of cancer deaths in the US, with a median survival time of less than 6 months. Most pancreatic cancer patients are diagnosed at an advanced stage when treatment options are not only extremely limited but ineffective. Therefore, understanding the etiology and identifying markers for early detection are a top priority for reducing its incidence and mortality.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate the translation of more than 60% of protein-coding genes and play a critical role in carcinogenesis and cancer progression., Emerging evidence suggests that pancreatic cancer patients have differentially expressed circulating miRNAs that may serve as early detection biomarkers. A recent JAMA article reported the discovery of 2 indices based on circulating miRNAs with an area under the curve(AUC) of 0.83 and 0.78(Index 1), 0.82 and 0.75(Index 2), respectively, for discrimination of cancer patients from healthy controls and chronic pancreatitis patients. The AUC increased to 0.94 and 0.83, 0.93 and 0.85 when the indices were combined with cancer antigen(CA) 19-9. Although these findings are very promising, the study was limited by using healthy young controls, measuring miRNA in whole blood, and including very few early-stage cases. Thus, they need to be replicated in more rigorously designed studies. Furthermore, the utility of these indices and other circulating miRNAs for early detection and risk assessment of pancreatic cancer need to be evaluated. To our knowledge, no miRNA markers have been confirmed in relation to pancreatic cancer risk. We propose to comprehensively evaluate the role of miRNAs for early detection and risk assessment by using pre-diagnostic serum/plasma samples of pancreatic cancer patients and normal controls from four prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian Cancer(PLCO) trial, Shanghai Women’s Health Study(SWHS), Shanghai Men’s Health Study(SMHS), and Southern Community Cohort Study(SCCS). We will also evaluate the utility of the two recently reported diagnostic indices for cancer diagnosis and early detection. The specific aims of the proposed study are:

Aim 1. To systematically evaluate 800 miRNAs in serum samples collected less than 3 years before cancer diagnosis from 100 pancreatic cancer cases and 200 age- and gender-matched controls from the PLCO to identify differentially expressed miRNAs for additional evaluation . We will also evaluate the miRNA diagnostic indices recently reported in JAMA for their utility in cancer early detection.

Aim 2. To evaluate promising miRNAs identified in Aim1 using pre-diagnostic serum samples from an additional 222 cases and 444 age- and gender-matched controls in the PLCO.

Aim 3. To evaluate the validated miRNAs in pre-diagnosis plasma samples of 450 cases and 900 matched controls from the SWHS, SMHS, and SCCS to evaluate the generalizability of the findings across ethnic populations .

-