• CCNB1IP1
• OLFM4
• gastric cancer

• Humans
• Stomach Neoplasms/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/metabolism
• Animals
• Cell Proliferation/genetics
• Mice
• Granulocyte Colony-Stimulating Factor/genetics
• Granulocyte Colony-Stimulating Factor/metabolism
• Adenocarcinoma/pathology
• Adenocarcinoma/genetics
• Adenocarcinoma/metabolism
• Gene Expression Regulation, Neoplastic
• Cell Line, Tumor
• MicroRNAs/genetics
• Xenograft Model Antitumor Assays
• Mice, Nude
• G2 Phase Cell Cycle Checkpoints/genetics
• Apoptosis
• Cyclin B1/metabolism

• NHLBI NIH HHS
• NIH HHS
• National Heart, Lung, and Blood Institute
• National Institutes of Health

• Caudal-type homeobox gene 2
• Gastric cancer
• Gastric intestinal metaplasia
• Nucleotide-binding oligomerization domain 1
• Olfactomedin 4
• Weiwei Decoction

• phagocytes
• immunoediting

• Humans
• Myeloid-Derived Suppressor Cells/metabolism
• Neoplasms/pathology
• Monocytes
• Neutrophils
• Carcinogenesis/metabolism
• Granulocyte Colony-Stimulating Factor

• 2021R1F1A1059826 National Research Foundation of Korea (NRF)
• 2022R1F1A1074547 National Research Foundation of Korea (NRF)

• GEO database
• Gastric intestinal metaplasia
• biomarker
• cBioPortal database
• gastric cancer

• OLFM4
• colorectal cancer
• olfactomedin 4
• stem cells
• stemness

Olfactomedin-4 (OLFM4) is an olfactomedin-domain-containing glycoprotein, which regulates cell adhesion, proliferation, gastrointestinal inflammation, innate immunity and cancer metastasis. In the present study we investigated its role in skin regeneration. We found that OLFM4 expression is transiently upregulated in the proliferative phase of cutaneous wound healing in humans as well as in mice. Moreover, a significant increase in OLFM4 expression was detected in the skin of lesional psoriasis, a chronic inflammatory disease characterized by keratinocyte hyperproliferation. In vitro experiments demonstrated that OLFM4 selectively stimulated keratinocyte proliferation and increased both keratinocyte and fibroblast migration. Using proteotranscriptomic pathway analysis we revealed that transcription factors POU5F1/OCT4 and ESR1 acted as hubs for OLFM4-induced signalling in keratinocytes. In vivo experiments utilizing mouse splinted full-thickness cutaneous wound healing model showed that application of recombinant OLFM4 protein can significantly improve wound healing efficacy. Taken together, our results suggest that OLFM4 acts as a transiently upregulated inflammatory signal that promotes wound healing by regulating both dermal and epidermal cell compartments of the skin.

• Keratinocytes
• Olfactomedin-4
• Psoriasis
• Skin burns
• Skin regeneration
• Wound healing

Detecting upper gastrointestinal (GI) cancers in primary care is challenging, as cancer symptoms are common, often non-specific, and most patients presenting with these symptoms will not have cancer. Substantial investment has been made to develop biomarkers for cancer detection, but few have reached routine clinical practice. We aimed to identify novel biomarkers for upper GI cancers which have been sufficiently validated to be ready for evaluation in low-prevalence populations.

We systematically searched MEDLINE, Embase, Emcare, and Web of Science for studies published in English from January 2000 to October 2019 (PROSPERO registration CRD42020165005). Reference lists of included studies were assessed. Studies had to report on second measures of diagnostic performance (beyond discovery phase) for biomarkers (single or in panels) used to detect pancreatic, oesophageal, gastric, and biliary tract cancers. We included all designs and excluded studies with less than 50 cases/controls. Data were extracted on types of biomarkers, populations and outcomes. Heterogeneity prevented pooling of outcomes.

We identified 149 eligible studies, involving 22,264 cancer cases and 49,474 controls. A total of 431 biomarkers were identified (183 microRNAs and other RNAs, 79 autoantibodies and other immunological markers, 119 other proteins, 36 metabolic markers, 6 circulating tumour DNA and 8 other). Over half (n = 231) were reported in pancreatic cancer studies. Only 35 biomarkers had been investigated in at least two studies, with reported outcomes for that individual marker for the same tumour type. Apolipoproteins (apoAII-AT and apoAII-ATQ), and pepsinogens (PGI and PGII) were the most promising biomarkers for pancreatic and gastric cancer, respectively.

Most novel biomarkers for the early detection of upper GI cancers are still at an early stage of matureness. Further evidence is needed on biomarker performance in low-prevalence populations, in addition to implementation and health economic studies, before extensive adoption into clinical practice can be recommended.

The online version of this article (10.1007/s12325-020-01571-z) contains supplementary material, which is available to authorized users.

• Biomarkers
• Clinical practice
• Early detection
• Primary care
• Upper gastrointestinal cancers

• Biomarkers
• Early Detection of Cancer
• Gastrointestinal Neoplasms/diagnosis
• Gastrointestinal Neoplasms/epidemiology
• Humans
• Pancreatic Neoplasms
• Prevalence

• Cancer Research UK (CRUK)

Neutrophils are a key component of inflammation in asthma. Olfactomedin 4 (OLFM4) is produced by neutrophils and has been reported to be associated with asthma inflammation. We hypothesized that serum OLFM4 may be increased in asthmatic individuals and can assist with predicting asthma control state.

A total of 79 individuals were enrolled from Shenzhen People’s Hospital, China and divided into 3 groups: uncontrolled asthmatics (n=35), controlled asthmatics (n=14), and healthy controls (n=30). The serum OLFM4 level was measured by enzyme-linked immunosorbent assay (ELISA). Clinical characteristics (such as age, gender, allergy history, body mass index (BIM), and smoking history), clinical indicators (such as whole blood count, sputum neutrophil, sputum eosinophil, forced expiratory volume in one second as percentage of predicted volume (FEV1% pred), IgE level, high sensitivity C-reactive protein (hs-CRP), and fractional expiratory nitric oxide (FeNO) were measured and the three groups were compared. The correlation between OLFM4 and the clinical characteristics and indicators was then evaluated. Finally, stepwise multiple regression analysis was performed to determine the contribution of clinical characteristics and clinical indicators influencing serum OLFM4 level.

Our results showed that the serum OLFM4 level was increased two-fold in the controlled asthma group (3,450.38±3,000.35 pg/mL) and three-fold in the uncontrolled asthma group (5,084.57±3,425.76 pg/mL), compared to the healthy control group (1,830.11±1,239.70 ng/mL) (P<0.001). We found a positive correlation between serum OLFM4 level and sputum neutrophils (P<0.001). OLFM4 was also found to be related to both hs-CRP level (P=0.007*) and blood neutrophil count (P<0.001). There were no significant associations identified between OLFM4 and age, gender, BMI, allergy, blood eosinophils, blood neutrophils, IgE, FeNO, or FEV1% pred.

Serum OLFM4 levels were increased in patients with asthma (the controlled asthma and uncontrolled asthma groups). There was a significant correlation between serum OLFM4 and levels of sputum neutrophil and hs-CRP, and OLFM4 was also related to both Hs-CRP level and blood neutrophil count. Serum OLFM4 level may serve as a useful biomarker for assessing asthma control state in asthmatic adults.

• Olfactomedin 4 (OLFM4)
• asthma
• biomarkers

• 5-FU
• Gastrointestinal cancers
• Reg4 protein
• cell proliferation
• phage library
• single-chain antibody.

Regenerating islet-derived (Reg) proteins have emerged as multifunctional agents with pro-proliferative, anti-apoptotic, differentiation-inducing and bactericidal properties. Over the last 40 years since first discovered, Reg proteins have been implicated in a gamut of maladies including diabetes, various types of cancer of the digestive tract, and Alzheimer disease. Surprisingly though, a consensus is still absent on the regulation of their expression, and molecular underpinning of their function. Here, we provide a critical appraisal of recent findings in the field of Reg protein biology. Specifically, the structural characteristics are reviewed particularly in connection with established or purported functions of different members of the Reg family. Moreover, Reg expression patterns in different tissues both under normal and pathophysiological conditions are summarized. Putative receptors and cascades reported to relay Reg signaling inciting cellular responses are presented aiming at a better appreciation of the biological activities of the distinct Reg moieties. Challenges are also discussed that have hampered thus far the rapid progress in this field such as the use of non-standard nomenclature for Reg molecules among various research groups, the existence of multiple Reg members with significant degree of homology and possibly compensatory modes of action, and the need for common assays with robust readouts of Reg activity. Coordinated research is warranted going forward, given that several research groups have independently linked Reg proteins to diseased states and raised the possibility that these biomolecules can serve as therapeutic targets and biomarkers.

• Reg proteins
• diabetes
• gastrointestinal cancer
• pancreas
• pancreatic adenocarcinoma

• Diverge
• Gene expression
• Olfactomedin
• Phylogenetic analysis
• SNP

• Cancer
• Helicobacter pylori infection
• Inflammation
• Olfactomedin-4

• Animals
• Biomarkers/metabolism
• Digestive System Neoplasms/drug therapy
• Digestive System Neoplasms/etiology
• Digestive System Neoplasms/mortality
• Digestive System Neoplasms/pathology
• Down-Regulation
• Gastrointestinal Diseases/drug therapy
• Gastrointestinal Diseases/etiology
• Gastrointestinal Diseases/mortality
• Gastrointestinal Diseases/pathology
• Gastrointestinal Tract/immunology
• Gastrointestinal Tract/microbiology
• Gastrointestinal Tract/pathology
• Glycoproteins/genetics
• Glycoproteins/immunology
• Glycoproteins/metabolism
• Granulocyte Colony-Stimulating Factor/genetics
• Granulocyte Colony-Stimulating Factor/immunology
• Granulocyte Colony-Stimulating Factor/metabolism
• Helicobacter Infections/drug therapy
• Helicobacter Infections/etiology
• Helicobacter Infections/pathology
• Helicobacter pylori/immunology
• Humans
• Mice
• Molecular Targeted Therapy/methods
• Prognosis
• Signal Transduction
• Survival Rate
• Up-Regulation

• Adenoma-carcinoma sequence
• Gastric adenoma
• Tumor-associated macrophages

• breast cancer
• circulating tumor cells
• olfactomedin 4
• plasma

Despite recent advances in colorectal cancer (CRC) diagnosis and population screening programs, the identification of patients with preneoplastic lesions or with early CRC stages remains challenging and is important for reducing CRC incidence and increasing patient’s survival.

We analysed 76 colorectal tissue samples originated from early CRC stages, normal or inflamed mucosa by label-free proteomics. The characterisation of three selected biomarker candidates was performed by immunohistochemistry on an independent set of precancerous and cancerous lesions harbouring increasing CRC stages.

Out of 5258 proteins identified, we obtained 561 proteins with a significant differential distribution among groups of patients and controls. KNG1, OLFM4 and Sec24C distributions were validated in tissues and showed different expression levels especially in the two early CRC stages compared to normal and preneoplastic tissues.

We highlighted three proteins that require further investigations to better characterise their role in early CRC carcinogenesis and their potential as early CRC markers.

The online version of this article (doi:10.1186/s12014-017-9143-3) contains supplementary material, which is available to authorized users.

• Bacterial infection
• Cancer
• Inflammation
• NF-κB
• Olfactomedin 4

A serum phosphopeptide (DpSGEGDFLAEGGGVR) was demonstrated to be a potential biomarker for gastric cancer diagnosis, particularly for early stage cases.

• Biomarker
• Breast cancer
• Metastasis
• Olfactomedin 4
• Prognosis

• NF-κB pathway
• NIK
• OLFM1
• colorectal cancer
• metastasis

• Animals
• Azacitidine/analogs & derivatives
• Azacitidine/pharmacology
• Biomarkers/metabolism
• Cell Line, Tumor
• Cell Proliferation
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• DNA Methylation
• Decitabine
• Disease-Free Survival
• Down-Regulation
• Enzyme Inhibitors/pharmacology
• Extracellular Matrix Proteins/genetics
• Extracellular Matrix Proteins/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• Glycoproteins/genetics
• Glycoproteins/metabolism
• Humans
• Liver Neoplasms/pathology
• Liver Neoplasms/secondary
• Lung Neoplasms/pathology
• Lung Neoplasms/secondary
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Middle Aged
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Prognosis
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• Signal Transduction
• NF-kappaB-Inducing Kinase

Downregulation of olfactomedin-4 (OLFM4) is associated with tumor progression, lymph node invasion and metastases. However, whether or not downregulation of OLFM4 is associated with epigenetic silencing remains unknown. In this study, we investigate the role of OLFM4 in gastric cancer cell invasion. We confirm the previous result that OLFM4 expression is increased in gastric cancer tissues and decreases with an increasing number of metastatic lymph nodes, which are associated with OLFM4 promoter hypermethylation. Overexpression of OLFM4 in gastric cancer cells had an inhibitory effect on cell invasion. Furthermore, we found that focal adhesion kinase (FAK) was negatively correlated with OLFM4 in regards to lymph node metastasis in gastric cancer tissues. Also, inhibition of FAK induced by OLFM4 knockdown resulted in a decrease in cell invasion. Thus, our study demonstrates that epigenetic silencing of OLFM4 enhances gastric cancer cell invasion via activation of FAK signaling. [BMB Reports 2015; 48(11): 630-635]

• biomarker
• oncogene
• oncology
• tumor suppressor
• tumorgenesis

Endoscopic surgery is increasingly used for early gastric cancer (EGC) treatment worldwide, and lymph node metastasis remains the most important risk factor for endoscopic surgery in EGC patients. Olfactomedin 4 (OLFM4) is mainly expressed in the digestive system and upregulated in several types of tumors. However, the role of OLFM4 in EGC has not been explored. We evaluated OLFM4 expression by immunohistochemical staining in 105 patients with EGC who underwent gastrectomy. The clinicopathological factors and OLFM4 expression were co-analyzed to predict lymph node metastasis in EGC. The metastatic mechanism of OLFM4 in gastric cancer was also investigated. We found that OLFM4 was upregulated in EGC tumor sections, and relatively low expression of OLFM4 was observed in patients with lymph node metastasis. OLFM4 expression as well as tumor size and differentiation were identified as independent factors, which could be co-analyzed to generate a better model for predicting lymph node metastasis in EGC patients. In vitro studies revealed that knockdown of OLFM4 promoted the migration of gastric cancer cells through activating the NF-κB/interleukin-8 axis. Negative correlation between OLFM4 and interleukin-8 expression was also observed in EGC tumor samples. Our study implies that OLFM4 expression is a potential predictor of lymph node metastasis in EGC, and combing OLFM4 with tumor size and differentiation could better stratify EGC patients with different risks of lymph node metastasis.

• Cell growth
• FKTN
• Fukutin
• Gastric cancer
• Mucin phenotype

Gastric cancer (GC) is a highly aggressive cancer type associated with significant mortality owing to delayed diagnosis and non-specific symptoms observed in the early stages. Therefore, identification of novel specific GC serum biomarkers for screening purposes is an urgent clinical requirement.

This study recruited a total of 432 serum samples from 296 GC patients split into the mining and testing sets. We aimed to screen for reliable protein biomarkers from matched serum samples based on mass spectrometry, followed by comparison with three representative conventional markers using receiver operating characteristic and survival curve analyses to ascertain their potential values as diagnostic and prognostic biomarkers for GC.

We identified an apoC-III fragment with confirmation in an independent test set from a second hospital. We found that the diagnostic ability of this fragment performed better than current standard GC diagnostic biomarkers both individually and in combination in distinguishing patients with GC from healthy individuals. Moreover, we found that this apoC-III protein fragment represents a more robust potential prognostic factor for GC than the three conventional markers.

In view of these findings, we suggest that apoC-III protein fragment is a novel diagnostic and prognostic biomarker, a complement to conventional biomarkers in detecting GC.

Olfactomedin 4 (OLFM4) is a secreted glycoprotein predominantly expressed in bone marrow and gastrointestinal tissues. Aberrant expression of OLFM4 has been shown in several cancers. However, the clinical significance hereof is currently controversial. OLFM4 has been proposed as a candidate biomarker of gastrointestinal cancers. To address this, we developed monoclonal antibodies against synthetic peptides representing various segments of OLFM4. We examined expression of OLFM4 in epithelial cells by immunohistochemistry and found that OLFM4 is highly expressed in proliferating benign epithelial cells and in some carcinoma cells. We developed an Enzyme Linked Immunosorbent Assay for OLFM4 and investigated whether plasma levels of OLFM4 reflect colorectal malignancies, but were unable to see any such association. Instead, we observed two populations of individuals with respect to OLFM4 levels in plasma, the majority with OLFM4 in plasma between 0 and 0.1 μg/ml, mean 0.028 μg/ml while 10% of both normals and patients with cancers had OLFM4 between 4 and 60 μg/ml, mean 15 μg/ml. The levels were constant over time. The background for this high plasma level is not known, but must be taken into account if OLFM4 is used as biomarker for GI cancers.

• colorectal cancer
• intestinal stem cells
• monoclonal antibodies
• neutrophil subsets
• olfactomedin 4

• Escherichia coli ampicillin secretion trap
• Serial Analysis of Gene Expression
• gastric cancer
• mucin
• phenotype

• Biomarker
• Extrahepatic cholangiocarcinoma
• Mass spectrometry
• Proteomics
• Scheduled selected reaction monitoring

• Aged
• Biomarkers, Tumor/analysis
• Carcinogenesis
• Granulocyte Colony-Stimulating Factor/biosynthesis
• Humans
• Immunohistochemistry
• In Situ Hybridization
• Kaplan-Meier Estimate
• Middle Aged
• Prognosis
• Real-Time Polymerase Chain Reaction
• Stomach Neoplasms/mortality
• Stomach Neoplasms/pathology
• Tissue Array Analysis

• gastric cancer
• g-factor
• molecular staging
• tnm classification

• Biomarkers, Tumor/analysis
• Biomarkers, Tumor/metabolism
• Claudins/metabolism
• Disease-Free Survival
• Female
• Humans
• Immunohistochemistry/methods
• Japan
• Kaplan-Meier Estimate
• Male
• Matrix Metalloproteinase 7/metabolism
• Neoplasm Staging
• Prognosis
• Receptor, ErbB-2/metabolism
• Societies, Scientific
• Stomach Neoplasms/classification
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/pathology
• Stomach Neoplasms/surgery
• Vascular Endothelial Growth Factor A/metabolism
• Vascular Endothelial Growth Factor C/metabolism

• Biomarker
• Cancer
• OLFM4
• Olfactomedin 4

Exercise is beneficial for a variety of age-related disorders. However, the molecular mechanisms mediating the beneficial adaptations to exercise in older adults are not well understood. The aim of the current study was to utilize a dual approach to characterize the genetic and metabolic adaptive pathways altered by exercise in veteran athletes and age-matched untrained individuals. Two groups of 50–60 year old males: competitive cyclists (athletes, n = 9; VO_2peak 59.1±5.2 ml·kg⁻¹·min⁻¹; peak aerobic power 383±39 W) and untrained, minimally active individuals (controls, n = 8; VO_2peak 35.9±9.7 ml·kg⁻¹·min⁻¹; peak aerobic power 230±57 W) were examined. All participants completed an acute bout of submaximal endurance exercise, and blood and urine samples pre- and post-exercise were analyzed for gene expression and metabolic changes utilizing genome-wide DNA microarray analysis and NMR spectroscopy-based metabolomics, respectively. Our results indicate distinct differences in gene and metabolite expression involving energy metabolism, lipids, insulin signaling and cardiovascular function between the two groups. These findings may lead to new insights into beneficial signaling pathways of healthy aging and help identify surrogate markers for monitoring exercise and training load.

• Adaptation, Physiological/genetics
• Aged
• Athletes
• Bicycling
• Case-Control Studies
• Energy Metabolism/genetics
• Exercise
• Gene Expression Regulation
• Humans
• Male
• Metabolome/genetics
• Middle Aged
• Oxygen Consumption/genetics
• Physical Endurance/genetics
• Signal Transduction
• Transcriptome

• OLFM4
• colorectal cancer
• glaucoma
• myocilin
• nervous system

• R01 AG073181 NIA NIH HHS
• R01 GM059469 NIGMS NIH HHS

Endometrial adenocarcinoma is the most common tumour of the female genital tract in developed countries, and oestrogen receptor (ER) signalling plays a pivotal role in its pathogenesis. When we used bioinformatics tools to search for the genes contributing to gynecological cancers, the expression of Olfactomedin 4 (OLFM4) was found by digital differential display to be associated with differentiation of endometrial adenocarcinoma. Aberrant expression of OLFM4 has been primarily reported in tumours of the digestive system. The mechanism of OLFM4 in tumuorigenesis is elusive. We investigated OLFM4 expression in endometrium, analysed the association of OLFM4 with ER signalling in endometrial adenocarcinoma, and examined the roles of OLFM4 in endometrial adenocarcinoma. Expression of OLFM4 was increased during endometrial carcinogenesis, linked to the differentiation of endometrioid adenocarcinoma, and positively related to the expression of oestrogen receptor-α (ERα) and progesterone receptor. Moreover, ERα-mediated signalling regulated expression of OLFM4, and knockdown of OLFM4 enhanced proliferation, migration and invasion of endometrial carcinoma cells. Down-regulation of OLFM4 was associated with decreased cumulative survival rate of patients with endometrioid adenocarcinoma. Our data suggested that impairment of ERα signal-mediated OLFM4 expression promoted the malignant progression of endometrioid adenocarcinoma, which may have significance for the therapy of this carcinoma.

• endometrial adenocarcinoma
• endometrial hyperplasia
• gynecological cancer
• oestrogen receptor (ER)
• olfactomedin 4 (OLFM4)

• colorectal cancer
• g-factor
• tnm classification
• molecular stage
• vegf-c
• reg iv

• Claudins/biosynthesis
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/surgery
• Disease-Free Survival
• Gene Expression Regulation, Neoplastic
• Granulocyte Colony-Stimulating Factor/biosynthesis
• Humans
• Lectins, C-Type/biosynthesis
• Lectins, C-Type/genetics
• Matrix Metalloproteinase 7/biosynthesis
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/pathology
• Neoplasm Staging
• Pancreatitis-Associated Proteins
• Vascular Endothelial Growth Factor A/biosynthesis
• Vascular Endothelial Growth Factor A/genetics
• Vascular Endothelial Growth Factor C/biosynthesis
• Vascular Endothelial Growth Factor C/genetics

The aim of this study was to identify key genes and novel potential therapeutic targets related to gastric cancer (GC) by comparing cancer tissue samples and healthy control samples using DNA microarray analysis.

Microarray data set GSE19804 was downloaded from Gene Expression Omnibus. Preprocessing and differential analysis were conducted with of R statistical software packages, and a number of differentially expressed genes (DEGs) were obtained. Cluster analysis was also done with gene expression values. Functional enrichment analysis was performed for all the DEGs with DAVID tools. The significantly up- and downregulated genes were selected out and their interactors were retrieved with STRING and HitPredict, followed by construction of networks. For all the genes in the two networks, GeneCodis was chosen for gene function annotation.

A total of 638 DEGs were identified, and we found that SPP1 and FABP4 were the markedly up- and downregulated genes, respectively. Cell cycle and regulation of proliferation were the most significantly overrepresented functional terms in up- and downregulated genes. In addition, extracellular matrix–receptor interaction was found to be significant in the SPP1-included interaction network.

A range of DEGs were obtained for GC. These genes not only provided insights into the pathogenesis of GC but also could develop into biomarkers for diagnosis or treatment.

The identification of new serum biomarkers with high sensitivity and specificity is an important priority in pancreatic cancer research. Through an extensive proteomics analysis of pancreatic cancer cell lines and pancreatic juice, we previously generated a list of candidate pancreatic cancer biomarkers. The present study details further validation of four of our previously identified candidates: regenerating islet-derived 1 beta (REG1B), syncollin (SYCN), anterior gradient homolog 2 protein (AGR2), and lysyl oxidase-like 2 (LOXL2).

The candidate biomarkers were validated using enzyme-linked immunosorbent assays in two sample sets of serum/plasma comprising a total of 432 samples (Sample Set A: pancreatic ductal adenocarcinoma (PDAC, n = 100), healthy (n = 92); Sample Set B: PDAC (n = 82), benign (n = 41), disease-free (n = 47), other cancers (n = 70)). Biomarker performance in distinguishing PDAC from each control group was assessed individually in the two sample sets. Subsequently, multiparametric modeling was applied to assess the ability of all possible two and three marker panels in distinguishing PDAC from disease-free controls. The models were generated using sample set B, and then validated in Sample Set A.

Individually, all markers were significantly elevated in PDAC compared to healthy controls in at least one sample set (p ≤ 0.01). SYCN, REG1B and AGR2 were also significantly elevated in PDAC compared to benign controls (p ≤ 0.01), and AGR2 was significantly elevated in PDAC compared to other cancers (p < 0.01). CA19.9 was also assessed. Individually, CA19.9 showed the greatest area under the curve (AUC) in receiver operating characteristic (ROC) analysis when compared to the tested candidates; however when analyzed in combination, three panels (CA19.9 + REG1B (AUC of 0.88), CA19.9 + SYCN + REG1B (AUC of 0.87) and CA19.9 + AGR2 + REG1B (AUC of 0.87)) showed an AUC that was significantly greater (p < 0.05) than that of CA19.9 alone (AUC of 0.82). In a comparison of early-stage (Stage I-II) PDAC to disease free controls, the combination of SYCN + REG1B + CA19.9 showed the greatest AUC in both sample sets, (AUC of 0.87 and 0.92 in Sets A and B, respectively).

Additional serum biomarkers, particularly SYCN and REG1B, when combined with CA19.9, show promise as improved diagnostic indicators of pancreatic cancer, which therefore warrants further validation.

• Bile
• Biomarker
• Olfactomedin-4
• Ras-related C3 botulinum toxin substrate 1
• Syntenin-2
• iTRAQ

• Adenocarcinoma/complications
• Adenocarcinoma/metabolism
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms/complications
• Bile Duct Neoplasms/metabolism
• Bile Ducts, Intrahepatic/metabolism
• Bile Ducts, Intrahepatic/pathology
• Biomarkers, Tumor/metabolism
• Cholangiocarcinoma/complications
• Cholangiocarcinoma/metabolism
• Cholestasis/diagnosis
• Cholestasis/etiology
• Cholestasis/metabolism
• Chromatography, Liquid
• Cohort Studies
• Female
• Humans
• Immunoblotting
• Male
• Middle Aged
• Pancreatic Neoplasms/complications
• Pancreatic Neoplasms/metabolism
• Pancreatitis, Chronic/complications
• Pancreatitis, Chronic/metabolism
• Proteomics/methods
• Tandem Mass Spectrometry