Micro RNA as a marker for prognosis in esophageal adenocarcinoma

This project is performed in collaboration with Dr’s James Luketich and Arjun Pennathur at the University of Pittsburgh.

This project is funded currently funded by the Department of Surgery at the University of Rochester Medical Center with an NIH R21 application pending.

Esophageal cancer occurs in two major histologic types; squamous cell carcinoma (SCC) and adenocarcinoma (AC). Although these tumors are often treated as one disease, they have distinct differences in epidemiology, risk factors and biological behavior. In Westernized countries the incidence of SCC has been steadily decreasing over the past 25 years while AC rates have increased dramatically. In fact, AC now has the fastest rate of increased incidence of any tumor in the United States. This is most likely linked to the rise in obesity and the prevalence of gastroesophageal reflux disease which is strongly linked to the development of AC.

While overall survival for esophageal cancer is historically poor, 5-yr survival for adenocarcinoma patients with surgically treatable disease can now approach 50%. Neoadjuvant therapy can provide an additional survival benefit in a subset of these patients but current methods for clinical staging do not accurately identify these individuals. We believe that molecular staging of pre-surgical tumor biopsies may predict disease recurrence and provide a better rationale for directing neoadjuvant therapy only to those patients who will not be cured by surgery alone. Our group is currently working on molecular staging approaches using messenger RNA expression and genomic DNA alterations for survival prediction. In the current proposal we will explore the association between microRNA expression and survival in the same large, well annotated patient cohort being used for these other studies.

MicroRNAs are small, non-coding, single stranded RNAs that bind to messenger RNAs and block protein translation. Furthermore, each microRNA can target many messenger RNAs and can therefore influence several genes within a single pathway, or impact genes in different pathways. Thus, microRNAs appear to be master regulators of protein levels in cells. MicroRNAs seem to play a particularly important role in differentiation and development and it is not surprising therefore, that microRNA deregulation has been implicated in cancer. There are now several reports of miRNA expression being linked to tumor initiation, proliferation, apoptosis, tumor progression and patient survival. Thus, microRNA expression may be a useful tool for molecular staging of tumors. In addition, approaches are being developed to target microRNAs as a novel molecular therapy. Clearly, microRNA expression studies have the potential to address important clinical problems in cancer. In this study, we propose to analyze microRNA expression in 150 tumors using a custom Affymetrix microRNA array. This array contains probes for all currently known human microRNAs as well as >1700 novel, computationally predicted microRNAs. Using these tools the primary goal of this proposal is to identify and validate individual microRNAs and microRNA expression signatures that are associated with patient survival in esophageal AC. In addition we will also integrate mRNA data from our other studies in order to explore the value of a combined mRNA/miRNA molecular staging approach to this disease.