ReviewStrategies for discovering novel pancreatic cancer biomarkers☆
Graphical abstract
Highlights
► The need for novel biomarkers to detect pancreatic cancer is emphasized. ► The discovery, usage and limitations of currently available markers are discussed. ► Strategies in discovering new markers for pancreatic cancer are discussed. ► Our integrated approach in identifying a panel of novel markers is outlined.
Introduction
Despite the increase in research interest and advancement in the understanding of pancreatic cancer over the past few decades, it remains one of the deadliest solid malignancies affecting mankind. It has a 5-year relative survival rate of less than 5%, a median survival rate of less than 6 months and is the fourth leading cause of cancer-related deaths in men and women in Canada and the United States despite being only the tenth most common form of cancer [1], [2]. The mortality is almost identical to its incidence rate for this devastating disease and it is estimated that there will be 43,920 new cases and 37,390 deaths from the disease in the U.S. in 2012 [1]. There are several types of pancreatic cancer, the most common being pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 90% of all pancreatic cancers [3] and for which this review will focus on.
The poor prognosis of PDAC is the result of its silent nature, high metastatic potential and resistance to conventional therapies. To date, the only potentially curative treatment is surgical resection, with the overall five-year survival rate improving to 40% if the tumor is detected at less than 20 mm and to 75% when tumors are detected at less than 10 mm [4]. Unfortunately only approximately 20% of the PDAC patients have their cancers detected at a stage at which surgical resection remains a viable option [5]. Once the disease has progressed into an advanced stage, chemotherapy, radiation or any combinatorial therapies are mostly palliative and have minimal improvement on the patient survival [6].
The inability to detect pancreatic cancer in its early treatable stage is a critical clinical problem. Unfortunately, early PDAC is characterized by a lack of clinical symptoms and when symptoms are present they are generally non-specific (back pain, weight loss, and digestive problems) and do not lead to disease detection. Although a standardized screening strategy is still maturing, the current screening practice commonly includes high risk individuals carrying genetic abnormalities associated with pancreatic cancer, with more than 2 first degree relatives diagnosed with pancreatic cancer, however, such patients only account for less than 5% of all pancreatic cancer [7]. Increasing evidences have shown that new-onset diabetes is present in approximately half of the pancreatic cancer patients, and its occurrence is prevalent even in early stage, asymptomatic pancreatic cancer patients [7]. Therefore, new-onset diabetes may represent a high risk population group to screen for asymptomatic pancreatic cancer [7]. Given that type 2 diabetes is common and pancreatic cancer is rare in the general population, screening all new-onset diabetic patients for pancreatic cancer is not cost-effective without a reliable marker to differentiate between pancreatic cancer-associated diabetes from the more prevalent type 2 diabetes [7]. There have been studies attempting to identify potential candidate biomarkers for pancreatic cancer-associated diabetes, however there is currently no specific marker available since they were either unsuccessful in consequent validation studies or remain to be validated [7], [8], [9], [10]. Even if such a marker is found, it may not detect pancreatic cancer in patients without pancreatic cancer-associated diabetes. This leads to the urgent need of the discovery and validation of biomarkers that can help detect PDAC at an early stage in all patients and improve the survival of pancreatic cancer patients.
Although it has been commonly believed that pancreatic cancer progresses and develops metastases too rapidly for early detection to be practical, new research indicates otherwise. Two recent studies analyzing the progression of PDAC using mathematical analyses of tumor genetic sequencing data showed that it may take up to about 10 years after tumor initiation for pancreatic cancer cells to acquire the metastatic capacity to spread to distant organs [11], [12]. Based on this finding, there appears to be a long window of opportunity for the detection of pancreatic cancer at an early stage, reinforcing the importance for researchers to discover and validate novel methods for the early detection of pancreatic cancer (Fig. 1).
Diagnostic tests of pancreatic cancer include computerized tomography (CT) scan, endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) [13], [14]. Owing to the fact that these imaging parameters are costly, potentially invasive and time consuming, they are usually performed only after the onset of symptoms. These imaging methods are powerful, yet they are not designed to detect early premalignant lesions, or PDAC when the tumor is small and potentially resectable. In addition, it is often difficult to differentiate chronic pancreatitis from pancreatic cancer. Due to their low cost, and minimal invasiveness, serum based biomarkers remain an ideal method for which to detect PDAC in its early stages. The past decade has seen a plethora of advancements in the field of proteomics, which coupled to the interest in early PDAC detection, and has led to numerous publications on the identification of potential biomarkers for clinical use in pancreatic cancer detection. This review focuses on the most widely used PDAC biomarker CA19-9, emerging novel protein markers and our identification of a biomarker panel using an integrative proteomic approach.
Section snippets
Conventional serum markers for pancreatic cancer
Current serum markers used for pancreatic cancer include carbohydrate antigen CA19-9 (Table 1) and carcinoembryonic antigen (CEA). Below we will discuss their discovery, performance characteristics and clinical utility. This will serve to highlight the usefulness of the currently available markers, while demonstrating the clear need for the identification of new markers.
The quest for novel pancreatic cancer biomarkers
Over the past two decades, vast effort and millions of dollars of investments have been contributed in hopes of discovering biomarkers that could perform clinically superior than CA19-9. Many papers have been reporting novel single markers that hold promise to revolutionize the diagnosis and management of pancreatic cancer. Most of these newly published biomarkers produce promising results in the initial discovery phase, but are either not adequately validated or reported to have unsuccessful
Emerging biomarkers
In the past 5 years, over 20 papers have been published reporting on the discovery of novel PDAC biomarkers. Most have not advanced past the initial discovery phase and have very little or no data supporting their clinical usefulness, however, others do have some data supporting their clinical usefulness and for which further validation studies are warranted. Below we will focus on several of these novel markers (Table 2).
DJ-1 was originally identified as a novel oncogene that transformed mouse
In-house integrative proteomics for the identification of pancreatic cancer biomarkers
Most discovery-phase papers report biomarkers identified from a single biological source. However, PDAC is a heterogeneous cancer, and thus no single biological material or model is able to recapitulate all aspects of the disease [60]. Using a single type of biological material for discovery will both limit the number of true biomarkers discovered as well as hinder the ability to identify and exclude false discoveries. Since every approach has its own advantages and disadvantages, we, and
Conclusion and future thoughts
Existing biomarkers for pancreatic cancer are neither sufficiently sensitive nor specific enough to detect early stage disease, or differentiate benign from malignant disease. Although some potential biomarkers show adequate sensitivity, most show poor specificity due to their elevation in other non-cancer specific diseases [60]. Additional serum biomarkers are urgently needed to improve on CA19-9 in pancreatic cancer diagnosis, given that the earlier the patient is diagnosed, the higher the
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2021, Journal of ProteomicsCitation Excerpt :Moreover, it is poorly expressed in early PDA stages and its levels can be also elevated in other pathologies such as obstructive jaundice, liver cirrhosis and inflammatory processes like pancreatitis [9,10]. In addition, CA 19–9 is not universally expressed in PDA because a percentage of the Caucasian population (7%–10% of general population) lacks a functional FUT3 allele (termed Lewis genotype negative Le a-b-), being the synthesis of CA 19–9 from the precursor carbohydrate antigen DUPAN-2 not possible in those patients and this consequently generates false-negative results [11–15]. Overall, to improve PDA patients' outcomes, there is an urgent need to find novel tumor markers that could overcome the limitations of the CA 19–9, allowing for the detection of PDA in the time-window between the initial mutations and the onset of cancer and distal metastasis.
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This article is part of a Special Issue entitled: From protein structures to clinical applications.