Molecular prognostic markers in pancreatic cancer

Abstract

Pancreatic cancer has a very poor prognosis and is a common cause of cancer death in the Western world. Certain genetic alterations may be important in the prognosis of pancreatic cancer. Activation mutations in the K- ras oncogene occur in around 90% of pancreatic cancers, and the overexpression of growth factors epidermal growth factor (EGF), transforming growth factor (TGF)alpha, TGFbetas 1-3, acidic fibroblast growth factor (aFGF), basic FGF (bFGF), and growth factor receptors c-erbB-2 and -3 and TGFRbetas 1-3 is common. High mutation levels of cell cycle control genes such as p53, p16, p21, SMAD4, and cyclin D1 are found, and there is abnormal expression of apoptotic genes, such as bcl-2, bcl-XL, and bax. The expression of several of these growth factors and their receptors has been found to be associated with poorly differentiated tumors of an advanced stage and decreased survival. However, the inactivation and loss of expression of p16, p53, and p21, and the expression of several apoptotic genes, such as bax and bcl-2, have not been found to be of any prognostic significance. The expression of wild type p53, however, may predict responsiveness to chemotherapy. TGFbeta1 expression has been shown to be associated with longer survival in patients with pancreatic cancer. Two studies (including our own) have found bcl-XL expression to be significantly associated with poor survival. These and newer molecular markers may prove to be important in the choice of future therapies for pancreatic cancer.

Association Between EGF, TGF-β1 and TNF-α Gene Polymorphisms and Hepatocellular Carcinoma

“…Many epithelial tumor entities including gastric and cervical cancer as well as cancers of head, neck, breast and lung express high levels of EGF, TGF-β1 and TNF-α, which are associated with advanced disease and poor clinical prognosis (Stuelten et al, 2005;Jakowlew et al, 2006;Van et al, 2006;Bussink et al, 2008;Wu et al, 2009). Higher level expression of EGF, TGF-β1 and TNF-α have been inversely correlated to survival in these patients and high expression levels have been found in advanced tumor stages (Friess et al, 1999;Ghaneh et al, 2002).…”

High EGFR mRNA expression is a prognostic factor for reduced survival in pancreatic cancer after gemcitabine-based adjuvant chemotherapy

“…There is increasing evidence showing the usefulness of immunohistochemical analysis of molecular markers, including EGFR, for predicting the clinical outcome of PDAC patients (10,11,13,25,26). Immunohistochemical analysis is a valid method as it shows protein expression.…”

Prognostic Significance of Activated Akt Expression in Pancreatic Ductal Adenocarcinoma

“…Although the conventional Tumor-Node-Metastasis staging system, which is defined by tumor size, tumor progression, lymph node involvement, and distant metastasis (15), is useful for PDAC classification, the outcome is poor for patients even in the low-stage (I and II) groups (5). Therefore, the prognostic use of several molecular markers for PDAC classification have been investigated (8), although none proved useful for predicting patient prognosis (9). We undertook the present study to determine whether Akt2, p-Akt, and p-ERK expression and the proliferation activity seen by Ki-67 LI are valid biological indicators of the aggressiveness of PDAC.…”

“…The altered expression of genes such as the K-ras oncogene frequently occurs during the development of PDAC (8). However, specific patterns of gene alternations responsible for PDAC have not been identified (9).…”