Current status of molecular markers for early detection of sporadic pancreatic cancer

Abstract

Pancreatic cancer (PC) is a highly lethal malignancy with near 100% mortality. This is in part due to the fact that most patients present with metastatic or locally advanced disease at the time of diagnosis. Significantly, in nearly 95% of PC patients there is neither an associated family history of PC nor of diseases known to be associated with an increased risk of PC. These groups of patients who comprise the bulk of PC cases are termed as "sporadic PC" in contrast to the familial PC cases that comprise only about 5% of all PCs. Given the insidious onset of the malignancy and its extreme resistance to chemo and radiotherapy, an abundance of research in recent years has focused on identifying biomarkers for the early detection of PC, specifically aiming at the sporadic PC cohort. However, while several studies have established that asymptomatic individuals with a positive family history of PC and those with certain heritable syndromes are candidates for PC screening, the role of screening in identifying sporadic PC is still an unsettled question. The present review attempts to assess this critical question by investigating the recent advances made in molecular markers with potential use in the early diagnosis of sporadic PC - the largest cohort of PC cases worldwide. It also outlines a novel yet simple risk factor based stratification system that could be potentially employed by clinicians to identify those individuals who are at an elevated risk for the development of sporadic PC and therefore candidates for screening.

Figure 1. Recent update on genes with a differential expression in the pre-malignant pancreatic intraepithelial neoplasia (PanIN) lesions

Pancreatic cancer develops from a series of premalignant lesions termed as PanINs. There are four grades of PanIN-PanIN 1a, 1b, 2 and 3. Genes that are differentially expressed in PanIN lesions hold significant potential in the early detection of adenocarcinoma of the pancreas. The figure shows genes that show a significant up- or downregulation in these precursor lesions compared to the non-neoplastic ducts of the pancreas. The gene name in the figure refers to its Entrez Gene ID (http://www.ncbi.nlm.nih.gov/gene). Those genes with a “*” sign beside them were identified as being upregulated three-fold or more in PanIN-3 lesions compared to the normal pancreas and were not expressed in chronic pancreatitis tissues. ^€ MUC5AC is strongly expressed in PanIN-1 lesions and this is maintained until invasive adenocarcinoma. ^¥ Based on reactivity to the PAM-4 monoclonal antibody to MUC1. ^£ Examination of S100P mRNA in micro dissected PanIN and PDAC tissues did not show any difference between PanIN and PDAC (Adapted from [,,–202]

Figure 2. Recent update on proteins differentially expressed between chronic pancreatitis and pancreatic cancer

A major problem in the early diagnosis of pancreatic cancer is the difficulty in distinguishing foci of adenocarcinoma in the setting of an underlying chronic pancreatitis. Further, the two processes share many genes that show a similar pattern of expression. The figure shows the genes that are differentially upregulated specifically in chronic pancreatitis (left) and pancreatic cancer (right). The symbols represents the HUGO names of the respective proteins (http://www.genenames.org/). Only proteins that were found to be up to fivefold or more are included. ^* Proteins whose expression was validated by quantitative real time RT-PCR. ^¥ Proteins that were validated by immunohistochemistry (Adapted from [203]).

Figure 3. Recent update on proteins whose expression correlates with tumor burden and clinical outcome in patients with pancreatic cancer

The prediction of tumor burden and early identification of recurrence remain two key challenges in patients with established pancreatic cancer. Proteins that can predict these events are immensely useful in devising prognostic algorithms, tailoring existing treatment strategies and devising new strategies for the treatment of pancreatic adenocarcinoma. The figure depicts proteins that have been identified as indicators of tumor burden (left) and recurrence or progression of disease (right) in pancreatic cancer. The unique NCBI identifiers for the proteins are as follows: CC3 (Protein accession number: NP_000055.2), C4A (GenBank: AAA51855.1), CFH (Swiss-Prot: P08603.4), A1BG (PIR: 69990), GC (NP_000574), APOA4 (GenBank: AAA51748.1), SERPINF1 (GenBank: AAA60058.1), HPX (GenBank: AAH05395.1), β-2 microglobulin (GenBank: CAA23830.1), α-2 macroglobulin (PRF: 224053), α-2 microglobulin (GenBank: CAI15899.1), Plasminogen (GenBank: AAH60513.1), α-2 HS glycoprotein (GenBank: BAA22651.1), Serum albumin precursor (GenBank: AAF01333.1), and C1q B-chain precursor (GenBank: CAA26880.1 (Adapted from [204])