Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls. We have profiled four miRNAs, miR-21, miR-210, miR-155, and miR-196a, all implicated in the development of pancreatic cancer with either proven or predicted target genes involved in critical cancer-associated cellular pathways. Of these, miR-155 has recently been identified as a candidate biomarker of early pancreatic neoplasia, whereas elevated expression of miR196a has been shown to parallel progression of disease. The results revealed a sensitivity of 64% and a specificity of 89% with the analyses of plasma levels for this panel of four miRNAs. The area under the receiver operating characteristic curve were estimated at 0.82 and 0.78 without and with leave-one-out cross-validation scheme, respectively. These observations, although a “proof of principle” finding at this time, show the feasibility of developing plasma miRNA profiling as a sensitive and specific blood-based biomarker assay for pancreatic cancer that has the potential of translation to the clinic with additional improvements in the future.

Numeric aberrations in chromosomes, referred to as aneuploidy, is commonly observed in human cancer. Whether aneuploidy is a cause or consequence of cancer has long been debated. Three lines of evidence now make a compelling case for aneuploidy being a discrete chromosome mutation event that contributes to malignant transformation and progression process. First, precise assay of chromosome aneuploidy in several primary tumors with in situ hybridization and comparative genomic hybridization techniques have revealed that specific chromosome aneusomies correlate with distinct tumor phenotypes. Second, aneuploid tumor cell lines and in vitro transformed rodent cells have been reported to display an elevated rate of chromosome instability, thereby indicating that aneuploidy is a dynamic chromosome mutation event associated with transformation of cells. Third, and most important, a number of mitotic genes regulating chromosome segregation have been found mutated in human cancer cells, implicating such mutations in induction of aneuploidy in tumors. Some of these gene mutations, possibly allowing unequal segregations of chromosomes, also cause tumorigenic transformation of cells in vitro. In this review, the recent publications investigating aneuploidy in human cancers, rate of chromosome instability in aneuploidy tumor cells, and genes implicated in regulating chromosome segregation found mutated in cancer cells are discussed.

MicroRNAs (miRNAs), the 17- to 25-nucleotide long noncoding RNAs that modulate the expression of mRNAs and proteins, have emerged as critical players in cancer initiation and progression processes. Deregulation of tissue miRNA expression levels associated with specific genetic alterations has been demonstrated in cancer, where miRNAs function either as oncogenes or as tumor-suppressor genes and are shed from cancer cells into circulation. The present review summarizes and evaluates recent advances in our understanding of the characteristics of tumor tissue miRNAs, circulating miRNAs, and the stability of miRNAs in tissues and their varying expression profiles in circulating tumor cells, and body fluids including blood plasma. These advances in knowledge have led to intense efforts towards discovery and validation of differentially expressing tumor-associated miRNAs as biomarkers and therapeutic targets of cancer. The development of tumor-specific miRNA signatures as cancer biomarkers detectable in malignant cells and body fluids should help with early detection and more effective therapeutic intervention for individual patients.