Noninvasive early markers in pancreatic cancer

Abstract

The development of early detection biomarkers is of special importance for pancreatic cancer, a devastating disease with poor prognosis and one of the most aggressive human malignancies. Despite considerable development in sophisticated imaging techniques and cytological examination, pancreatic cancer is most often diagnosed late in the course of the disease, after local spread and distant metastases have already occurred. Since pancreatic cancer is very difficult to treat, the key to the management of this disease are understanding of the molecular basis of transformation into malignant tumor of the pancreas and identification of molecular markers that can be used for early detection of the disease in the clinical practice. Although many molecular markers have been examined in pancreatic cancer, none are considered to be sufficiently specific and sensitive for preoperative diagnosis. Altered serum levels of CA 19-9 and mutated K-RAS gene are often used in clinical practice as markers of pancreatic malignancy. However, their sensitivity and specificity are relatively low and the use of other markers in combination with these two is necessary to improve diagnostic accuracy. Of several tumor suppressor genes inactivated in pancreatic tumors, SMAD4 genetic alterations appear to be the landmark of pancreatic tumorigenesis and they may prove to have high diagnostic value for this type of malignancy. Latest studies are directed toward the discovery of altered levels of proteins other than CA 19-9 and other molecules in serum samples of pancreatic cancer patients as early markers of malignant process. Diagnostics based on such markers would be noninvasive, and these markers would also be useful for disease monitoring and assessment of the response to therapy. However, altered serum levels of proteins and other molecules are not reliable diagnostic markers, since they may vary due to factors other than malignancy, inflammation above all. Genetic and epigenetic markers are much more reliable, but their analysis currently requires tumor tissue samples, which can only be obtained during invasive procedures, such as surgical procedure or biopsy. Considering the previously mentioned limitations, the most promising approach in early diagnosis of pancreatic cancer appears to be the analysis of circulating DNA in serum samples of pancreatic cancer patients. Fragments of DNA released in the blood flow of patients with malignancy by necrotic pancreatic cancer cells represent the largest portion of cell-free DNA. Since cell-free DNA reflects the genetic status of the tumor, it can be analyzed for the presence of mutations in specific genes and for methylation of various gene promoters, which would produce the most accurate and specific diagnostic information. Methodological improvements in molecular diagnosis of pancreatic cancer remain to change the way this disease is discovered and treated.