Genetic alterations in pancreatic carcinoma

Abstract

Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.

Figure 1

The INK4a/ARF locus. The two products of the INK4a/ARF locus encodes for p16^INK4a and p14^ARF (p19^Arf in mice). p16^INK4a indirectly regulates RB function and p14^ARF indirectly stabilizes p53.

Figure 2

Interplay of the major genetic alteration in pancreatic carcinoma with the cell cycle. All four major genetic alteration, K-RAS, INK4a, TP53 and the TGF-β/SMAD4 tumor suppressor pathway, observed in pancreatic carcinoma, regulate directly or indirectly G1 progression, leading to E2F dependent S phase entry.