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Both serology-based and genetic studies have reported an association between pancreatic cancer risk and ABO blood groups. We have investigated this relationship in a cohort of pancreatic cancer patients from Western Norway (n = 237) and two control materials (healthy blood donors, n = 379; unselected hospitalized patients, n = 6149). When comparing patient and blood donor ABO allele frequencies, we found only the A 1 allele to be associated with significantly higher risk for pancreatic ductal adenocarcinoma (PDAC) (23.8% vs. 17.9%; OR = 1.43, P = 0.018). Analyzing phenotypes, blood group A was more frequent among PDAC cases than blood donors (50.8% vs. 40.6%; OR = 1.51, P = 0.021), an enrichment fully explained by the A 1 subgroup. Blood group O frequency was lower in cases than in blood donors (33.8% vs. 42.7%; OR = 0.69, P = 0.039). This lower frequency was confirmed when cases were compared to hospitalized patients (33.8% vs. 42.9%; OR = 0.68, P = 0.012). Results for blood group B varied according to which control cohort was used for comparison. When patients were classified according to surgical treatment, the enrichment of blood group A was most prominent among unresected cases (54.0%), who also had the lowest prevalence of O (28.7%). There was a statistically significant better survival (P = 0.04) for blood group O cases than non-O cases among unresected but not among resected patients. Secretor status did not show an association with PDAC or survival. Our study demonstrates that pancreatic cancer risk is influenced by ABO status, in particular blood groups O and A 1 , and that this association may reflect also in tumor resectability and survival., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/objectives: We have recently described copy number variants (CNVs) of the human carboxyl-ester lipase (CEL) gene, including a recombined deletion allele (CEL-HYB) that is a genetic risk factor for chronic pancreatitis. Associations with pancreatic disease have also been reported for the variable number of tandem repeat (VNTR) region located in CEL exon 11. Here, we examined if CEL CNVs and VNTR length polymorphisms affect the risk for developing pancreatic cancer., Methods: CEL CNVs and VNTR were genotyped in a German family with non-alcoholic chronic pancreatitis and pancreatic cancer, in 265 German and 197 Norwegian patients diagnosed with pancreatic adenocarcinoma, and in 882 controls. CNV screening was performed using PCR assays followed by agarose gel electrophoresis whereas VNTR lengths were determined by DNA fragment analysis., Results: The investigated family was CEL-HYB-positive. However, an association of CEL-HYB or a duplication CEL allele with pancreatic cancer was not seen in our two patient cohorts. The frequency of the 23-repeat VNTR allele was borderline significant in Norwegian cases compared to controls (1.2% vs. 0.3%; P = 0.05). For all other VNTR lengths, no statistically significant difference in frequency was observed. Moreover, no association with pancreatic cancer was detected when CEL VNTR lengths were pooled into groups of short, normal or long alleles., Conclusions: We could not demonstrate an association between CEL CNVs and pancreatic cancer. An association is also unlikely for CEL VNTR lengths, although analyses in larger materials are necessary to completely exclude an effect of rare VNTR alleles., (Copyright © 2016 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

In pancreatic ductal adenocarcinoma (PDAC), the benefit of current chemotherapy and radiation therapy is very limited, even in radically resected patients. New treatment strategies, for example based on the inhibition of the tumour's blood supply, need to be explored. We have investigated angiogenesis markers and their associations with relapse and survival in 52 histologically confirmed cases of PDAC. Angiogenesis in the primary tumour was evaluated by microvessel density (MVD), vascular proliferation index (VPI) and the presence of glomeruloid microvascular proliferations (GMP). These features were analysed in the context of clinicopathological variables, KRAS mutation status, relapse location and survival. MVD (median 134 microvessels/mm(2) , range 88-177) and VPI (median 3.2%, range 1.6-4.9) were associated with larger tumour size and lymph node metastasis. MVD was also related to the occurrence of liver metastases. Both variables were associated with survival in univariate and multivariate analyses. GMPs were present in 32 (62%) of the cases. Patients who exhibited MVD and VPI values above median, and GMP positivity, had a median survival of only 4.2 months after surgery. In conclusion, the angiogenesis markers MVD and VPI have a significant impact on survival. By also including GMP, a subgroup of PDAC patients with particularly short survival could be identified., (© 2013 APMIS Published by John Wiley & Sons Ltd.)

Tumor-initiating cells of pancreatic ductal adenocarcinoma (PDAC) have been isolated based on expression of either CD133 or CD44. The authors aimed to visualize pancreatic cells simultaneously expressing both these cell surface markers by employing the same antibodies commonly used in cell-sorting studies. Normal and diseased pancreatic tissue, including 51 PDAC cases, were analyzed. CD44 and CD133 expression was determined by immunohistochemical double staining on formalin-fixed material and subcellular protein distribution evaluated by immunofluorescence/confocal microscopy. In the normal pancreas, CD44 and CD133 were coexpressed in the centroacinar regions but in non-overlapping subcellular compartments. As expected, CD44 was found mainly basolaterally, whereas CD133 was present on the apical/endoluminal membrane. This was also the case in chronically inflamed/atrophic pancreatic tissue and in PDAC. In some malignant ducts, CD44 was found at the apical cell membrane adjacent to but never overlapping with CD133 expression. CD44 level was significantly associated with the patient's lymph node status. In conclusion, a CD44+/CD133+ cell population does exist in the normal and neoplastic pancreas. The preferentially centroacinar localization of the doubly positive cells in the normal parenchyma suggests that this population could be of particular interest in attempts to identify tumor-initiating cells in PDAC.

Background: It has been suggested that a small population of cells with unique self-renewal properties and malignant potential exists in solid tumors. Such "cancer stem cells" have been isolated by flow cytometry, followed by xenograft studies of their tumor-initiating properties. A frequently used sorting marker in these experiments is the cell surface protein CD133 (prominin-1). The aim of this work was to examine the distribution of CD133 in pancreatic exocrine cancer., Methods: Fifty-one cases of pancreatic ductal adenocarcinomas were clinically and histopathologically evaluated, and immunohistochemically investigated for expression of CD133, cytokeratin 19 and chromogranin A. The results were interpreted on the background of CD133 expression in normal pancreas and other normal and malignant human tissues., Results: CD133 positivity could not be related to a specific embryonic layer of organ origin and was seen mainly at the apical/endoluminal surface of non-squamous, glandular epithelia and of malignant cells in ductal arrangement. Cytoplasmic CD133 staining was observed in some non-epithelial malignancies. In the pancreas, we found CD133 expressed on the apical membrane of ductal cells. In a small subset of ductal cells and in cells in centroacinar position, we also observed expression in the cytoplasm. Pancreatic ductal adenocarcinomas showed a varying degree of apical cell surface CD133 expression, and cytoplasmic staining in a few tumor cells was noted. There was no correlation between the level of CD133 expression and patient survival., Conclusion: Neither in the pancreas nor in the other investigated organs can CD133 membrane expression alone be a criterion for "stemness". However, there was an interesting difference in subcellular localization with a minor cell population in normal and malignant pancreatic tissue showing cytoplasmic expression. Moreover, since CD133 was expressed in shed ductal cells of pancreatic tumors and was found on the surface of tumor cells in vessels, this molecule may have a potential as clinical marker in patients suffering from pancreatic cancer.

The vast majority of tumors of the pancreas are ductal adenocarcinomas. This cancer type has an extremely poor prognosis and in many Western countries, it represents the fifth leading cause of cancer-related death. Pancreatic ductal adenocarcinomas exhibit the highest incidence of activating KRAS (Ki-Ras) mutations observed in any human cancer. It was therefore of interest to examine how this pattern would relate to mutations in the BRAF and EGFR genes, which are involved in the same signaling pathway as KRAS. We screened a series of 43 formalin-fixed, paraffin-embedded ductal adenocarcinomas of the pancreas. When DNA was extracted from whole tissue sections, KRAS codon 12 mutations were detected in 67% of the tumors. When cancerous ducts were isolated by laser-assisted microdissection, 91% were positive for KRAS mutations. Although it did not reach statistical significance, there was a trend in our material that survival after diagnosis varied according to KRAS mutation subtype, GTT-positive patients having the best prognosis. No alterations in BRAF exons 11 and 15 or in EGFR exons 18-21 were detected in KRAS-positive or KRAS-negative cases. We therefore conclude that the BRAF and EGFR mutations commonly seen in a variety of human cancers are generally absent from pancreatic ductal adenocarcinomas. Apparently, these tumors depend on no more than one genetic hit in the EGFR-RAS-RAF signaling pathway.

Background: Pancreatic adenocarcinoma is a relatively frequent cancer with an extremely poor prognosis. Until recently, the natural history of pancreatic adenocarcinoma has not been possible to study, but the identification of precursor lesions (pancreatic intraepithelial neoplasia, PanIN) has lead to a better understanding of the stepwise morphological and genetic alterations involved in the development of invasive adenocarcinoma., Material and Methods: Relevant literature from the period of 1996-2005 was found by searching the Medline database, combining the terms "pancreas", "cancer", "PanIN" and "neoplasia". Principal original and review papers were extracted and used as background for a presentation of the PanIN cancer progression model., Results and Interpretation: PanINs are established as designation of histological precursor lesions to pancreatic adenocarcinoma. PanIN grade I to III represent stepwise morphological alterations in the pancreatic ductal epithelium, from early neoplasia (PanIN I and II), via carcinoma in situ (PanIN III) to the development of invasive ductal adenocarcinoma. This model allows for the investigation of sequential molecular changes such as activation of oncogenes and inactivation of tumour suppressor genes. Increased knowledge about pancreatic carcinogenesis may pave the way for prevention strategies, early detection, and new treatment options, thus ultimately improving the prognosis of the patients.