© Springer-Verlag Berlin Heidelberg 2017
Sun-Whe Kim and Hiroki Yamaue (eds.)Pancreatic Cancer10.1007/978-3-662-47181-4_66. Tumor Markers
(1)
Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
6.1 Protein Markers
6.1.1 Carbohydrate Antigen 19-9 (CA 19-9)
The most widely used serum tumor marker is carbohydrate antigen 19-9 (CA 19-9).
The synthesis and expression of CA 19-9 depend on fucosyltransferase-2 and 3 activity. Approximately, 5–7% of general populations are unable to express CA 19-9 because they lack fucosyltransferase-3 activity (Lewis antigen negative). So, it is well reported that up to 15% of patients with an advanced stage have a normal CA 19-9 level. In addition, the levels are usually normal in the early stage and falsely elevated in patients with many kinds of benign conditions such as pancreatitis, cholangitis, and obstructive jaundice. Therefore, CA 19-9 has a roughly 80% sensitivity and 85% specificity for the diagnosis of pancreatic cancer [1]. Another important point is relatively low incidence of pancreatic cancer in general population (~10/100,000). Because the positive predictive value of CA 19-9 is extremely low, the screening is not cost-effective, and CA 19-9 is not recommended as a screening tool. In current practice, the roles of CA 19-9 are only restricted to detection of tumor recurrence after curative surgery [2] and prediction of prognosis after surgical resection or chemotherapy [3].
6.1.2 Carcinoembryonic Antigen (CEA)
Carcinoembryonic antigen (CEA) is another commonly used tumor marker for pancreatic cancer. CEA has a roughly 54% sensitivity and 79% specificity for the diagnosis of pancreatic cancer [4]. Therefore, the diagnostic accuracy of CEA is lower than that of CA 19-9. When CEA is used in conjunction with CA 19-9, the sensitivity and specificity can be changed to 86% and 72%, respectively [4]. So, CEA can be used in pancreatic cancer patients with normal CA 19-9 level as a prognostic marker in patients after surgical resection.
6.1.3 Others
Other reported tumor markers include CA 125 [5], CECAM-1 [6], MUC1 [7], and osteopontin [8], but the clinical utility of theses markers is undetermined and requires further validation studies. Recently, several novel markers are reported as potential candidate diagnostic biomarkers. They include intercellular adhesion molecule-1, macrophage inhibitory cytokine-1, osteoprotegerin, tissue inhibitor of metalloproteinase-1, and S100 calcium-binding protein P (S100P). A meta-analysis reported that pooled sensitivity and specificity of S100P are 87% and 88%, respectively [9]. Further studies are necessary to define clinical significance of these novel candidate biomarkers.
6.2 DNA
6.2.1 Genetic Alterations
Commonly mutated genes in pancreatic cancers are known to be KRAS, P53, CDKN2, and SMAD4. The recent whole genome sequencing analysis of 100 patients with pancreatic cancer demonstrated that KRAS mutation was detected in almost all patients and the prevalence of other gene mutations was 74% for P53, 35% for CDKN2, and 31% for SMAD4 [10]. Although KRAS mutation seems to be an ideal tumor marker, a plasma assay lacks both sensitivity and specificity because of its insensitivity in the detection of early pancreatic cancer [11] and frequent detection in patients with chronic pancreatitis and smokers. Therefore, none of the DNA markers have demonstrated a promising outcome as a tumor marker in clinical practice. However, KRAS mutation analysis in samples of endoscopic ultrasound (EUS)-guided fine-needle aspirate (FNA) can be used as a good biomarker. A meta-analysis of eight prospective studies reported that sensitivity and specificity of KRAS mutation analysis in conjunction with cytology of EUS-guided FNA were 88.7% and 92% which are better than cytology alone [12]. Some studies investigated the feasibility of detecting DNA markers in stool and reported that KRAS mutation was detected in 67% of in patients with pancreatic cancer [13]. In the future, a very low level of circulating mutated DNA can be detected easily with high sensitivity due to the development of next-generation sequencing and innovative technologies, and a novel DNA marker will be developed.
6.2.2 Epigenetic Alterations
The aberrant methylation-mediated functional loss of tumor suppressor genes has been detected in all kinds of cancers including pancreatic cancer, and these changes are rarely detected in normal tissues. There are many cancer-related genes with aberrant methylation that play roles in pancreatic cancer carcinogenesis which include CDKN2A, MLH1, CDH1, SPARC, DUSP6, RELN, RASSF1A, CCND2, TFPI2, RUNX3, SOCS1, and TSLC1 [14].
Many of these aberrantly methylated genes are present frequently in pancreatic cancers and can be easily detected with methylation-specific PCR analysis which makes them attractive candidates for an early diagnosis of pancreatic cancer. This hypermethylation can be analyzed in pancreatic juice and EUS-FNA samples and be a promising biomarker for the diagnosis of pancreatic cancer [15]. There are several studies of hypermethylation analysis in blood samples [16]. All studies are based on the methylation status of a single or a few gene panels in small number of patients. No single gene has been reported to have good sensitivity and specificity, suggesting that a panel of several genes is necessary as a tumor marker for pancreatic cancer. Further researches are necessary in order to clinically apply these markers based on hypermethylation for pancreatic cancer.
6.3 MicroRNA
MicroRNAs (miRNAs) are small, single-stranded noncoding RNAs consisting of 18–22 nucleotides that control the post-transcriptional expression of many kinds of genes. The miRNAs have an important role in carcinogenesis by targeting the matched mRNA, and a single miRNA can control the expression of many genes. Because miRNA dysregulation is specific not only to tissue but also to cancer, the altered miRNA expression profile can be a good biomarker for cancer and an attractive therapeutic molecular target. Many studies have already demonstrated that miRNAs are highly deregulated in pancreatic cancer tissues. Some miRNAs are upregulated and others are downregulated. They are associated with pancreatic cancer cell proliferation, survival, chemoresistance, and metastasis [17]. Many recent studies focused on their diagnostic and prognostic biomarkers in pancreatic cancer. Some studies have already demonstrated in 2008 that miRNAs released from cancer tissue were detected in blood even after freezing and suggested circulating miRNAs can be a promising biomarker for cancer detection [18]. In pancreatic cancer, several earlier studies focused on blood miRNA profiles to discriminate between patients with pancreatic cancer and normal controls. miR-21, miR-155, miR-196a, and miR-210 all of which have been known to be upregulated in pancreatic cancer tissue were suggested as a blood candidate biomarker [19]. The recent Danish study investigated miRNA expression profiles in blood of 409 patients with pancreatic cancer. This study identified two miRNA panels consisting of sets of four (miR-145, miR-150, miR-223, miR-636) and ten miRNAs (miR-26b, miR-34a, miR-122, miR-126, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p) that discriminate between patients with pancreatic cancer and normal controls [20].
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