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1. Serum Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor-binding Protein 2 as a Novel Biomarker in the Detection of Pancreatic Adenocarcinoma.

Author

Wlodarczyk B, Borkowska A, Wlodarczyk P, Malecka-Panas E, and Gasiorowska A

Subjects
Biomarkers, Humans, Insulin-Like Growth Factor Binding Protein 2, Insulin-Like Growth Factor I metabolism, Adenocarcinoma diagnosis, Pancreatic Neoplasms diagnosis
Abstract

Background: Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) are proteins that belong to the IGF axis, which is involved in glucose and lipid metabolism and may as well promote carcinogenesis., Goals: The aim of this study was to evaluate the serum concentration levels of IGF-1 and IGFBP-2 in patients with newly diagnosed pancreatic adenocarcinoma (PDAC) to verify their possible role in the diagnosis of the disease., Study: The study included 69 patients with PDAC and 20 healthy controls. The concentrations of IGF-1 and IGFBP-2 were estimated by means of ELISA. The study protocol was approved by the Bioethics Committee at the Medical University of Lodz in Poland., Results: PDAC patients compared with controls have a significantly lower mean serum IGF-1 level (45.83±30.03 vs. 70.66±60.57 ng/mL; P<0.0001). In contrast, in PDAC patients, the mean IGFBP-2 level was significantly higher compared with the control group (225.06±86.37 vs. 51.92±29.40 ng/mL; P<0.0001). The results show that, at the 0.01 sensitivity level, the IGF-1/IGFBP-2 ratio <0.85 points indicates PDAC presence. At this level of sensitivity, the test has a specificity of 0.097 (α=0.01; β=0.097; IGF-1/IGFBP-2≤0.85)., Conclusions: Our results show that IGF-1 to IGFBP-2 ratio ≤0.85 may be a powerful PDAC indicator. Further studies in this area in a larger patient group are necessary to confirm our findings.

Published
2020
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2. Clinical significance of activin A and myostatin in patients with pancreatic adenocarcinoma and progressive weight loss.

Author

Talar-Wojnarowska R, Wozniak M, Borkowska A, Olakowski M, and Malecka-Panas E

Subjects
Adenocarcinoma diagnosis, Aged, Aged, 80 and over, Biomarkers, Tumor blood, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms diagnosis, Prospective Studies, Activins blood, Adenocarcinoma blood, Disease Progression, Myostatin blood, Pancreatic Neoplasms blood, Weight Loss physiology
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive weight loss and nutritional deterioration. Several cytokines, such as activin A and myostatin, ligands of the transforming growth factor-β superfamily, have been shown to influence the pathogenesis of muscle wasting and tumor progression. The aim of our study was to assess the clinical significance of these cytokines in patients with different stages of PDAC. The study included 93 patients: 73 with newly diagnosed PDAC and 20 healthy volunteers as the control group. PDAC patients included 42 diagnosed with non-metastatic pancreatic cancer (stage I - III) and 31 patients with metastatic cancer (stage IV). The peripheral venous blood samples were collected from each patients at the time of cancer diagnosis and plasma concentrations of activin A and myostatin have been measured with an enzyme-linked immunoassay. Forty five patients (61.6%) presented weight loss > 5%, including 24 (57.1%) with stage I - II and 21 (67.7%) with metastatic PDAC (P > 0.05). Plasma levels of activing A were significantly higher in metastatic PDAC patients compared with stage I - III PDAC patients and control group (P < 0.01). The relationship between higher activin A levels and weight loss was also observed (P < 0.05). On the other hand, myostatin was not associated with weight loss in analysed group of patients. In conclusion, the current study demonstrates that high activin A plasma levels at the time of PDAC diagnosis is associated with unintentional weight loss and may be an useful biomarker for identifying patients with metastatic disease. However, further prospective studies are needed to fully explore the clinical significance of myostatin in pathogenesis of progressive weight loss in PDAC patients.

Published
2020
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3. The Role of Insulin-like Growth Factor (IGF) Axis in Early Diagnosis of Pancreatic Adenocarcinoma (PDAC).

Author

Wlodarczyk B, Gasiorowska A, and Malecka-Panas E

Subjects
Animals, Carcinoma, Pancreatic Ductal epidemiology, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal surgery, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 surgery, Humans, Inflammation Mediators metabolism, Insulin Resistance, Lipid Metabolism, Pancreatectomy, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Paraneoplastic Syndromes epidemiology, Paraneoplastic Syndromes pathology, Paraneoplastic Syndromes surgery, Risk Factors, Signal Transduction, Treatment Outcome, Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal metabolism, Diabetes Mellitus, Type 2 metabolism, Insulin-Like Growth Factor Binding Proteins metabolism, Insulin-Like Growth Factor I metabolism, Pancreatic Neoplasms metabolism, Paraneoplastic Syndromes metabolism, Receptors, Somatomedin metabolism
Abstract

New-onset diabetes mellitus (DM) is one of the first symptoms of pancreatic adenocarcinoma (PDAC). The frequency of endocrine disorders is estimated between 40% and 80% in patients with pancreatic cancer. DM is a risk factor for cancer development but it may also be a consequence of the tumor growth. Data confirming the existence of a relationship between long standing type 2 DM and an increased risk of PDAC comes from numerous clinical studies. Insulin resistance phenomenon and hyperinsulinemia may result in the increased proliferation of pancreatic islets which in turn may cause a predisposition to cancer development. In contrast, it is proved that new-onset DM among patients over 50 years old significantly increases the risk of PDAC recognition. Insulin-like growth factor 1 (IGF-1) and their complex proteins, IGF binding proteins, which comprise the IGF axis play a crucial role in carbohydrate metabolism disorders and, studies have shown that they may contribute to PDAC growth. Some studies confirm that IGF-1 is connected with early carcinogenesis in animals and humans. Assessing the levels of these proteins may thus be helpful in early recognition of PDAC in patients with recently detected endocrine disorders, especially pancreatic DM.

Published
2018
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4. Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms.

Author

Obazee O, Capurso G, Tavano F, Archibugi L, De Bonis A, Greenhalf W, Key T, Pasquali C, Milanetto AC, Hackert T, Fogar P, Liço V, Dervenis C, Lawlor RT, Landoni L, Gazouli M, Zambon CF, Funel N, Strobel O, Jamroziak K, Cantù C, Malecka-Panas E, Landi S, Neoptolemos JP, Basso D, Talar-Wojnarowska R, Rinzivillo M, Andriulli A, Canzian F, and Campa D

Subjects
Adult, Aged, Biomarkers, Tumor genetics, Female, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Carcinoma, Neuroendocrine genetics, Carcinoma, Pancreatic Ductal genetics, Genetic Predisposition to Disease genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide genetics
Abstract

Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.

Published
2018
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5. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.

Author

Campa D, Pastore M, Capurso G, Hackert T, Di Leo M, Izbicki JR, Khaw KT, Gioffreda D, Kupcinskas J, Pasquali C, Macinga P, Kaaks R, Stigliano S, Peeters PH, Key TJ, Talar-Wojnarowska R, Vodicka P, Valente R, Vashist YK, Salvia R, Papaconstantinou I, Shimizu Y, Valsuani C, Zambon CF, Gazouli M, Valantiene I, Niesen W, Mohelnikova-Duchonova B, Hara K, Soucek P, Malecka-Panas E, Bueno-de-Mesquita HBA, Johnson T, Brenner H, Tavano F, Fogar P, Ito H, Sperti C, Butterbach K, Latiano A, Andriulli A, Cavestro GM, Busch ORC, Dijk F, Greenhalf W, Matsuo K, Lombardo C, Strobel O, König AK, Cuk K, Strothmann H, Katzke V, Cantore M, Mambrini A, Oliverius M, Pezzilli R, Landi S, and Canzian F

Subjects
Adenocarcinoma genetics, Adenocarcinoma pathology, Adult, Aged, Carcinoma, Pancreatic Ductal pathology, Case-Control Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Nuclear Proteins genetics, Pancreatic Neoplasms pathology, Pancreatitis, Chronic pathology, Prognosis, Retrospective Studies, Risk Factors, Trypsin genetics, Trypsinogen genetics, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal genetics, Pancreatic Neoplasms genetics, Pancreatitis, Chronic genetics, Polymorphism, Single Nucleotide
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (OR homozygous  = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (OR heterozygous  = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10 -6 ) and MORC4-rs 12837024 (OR homozygous  = 2.07 (1.55-2.77, p trend  = 0.7 × 10 -11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants., (© 2017 UICC.)

Published
2018
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6. SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival.

Author

Mohelnikova-Duchonova B, Strouhal O, Hughes DJ, Holcatova I, Oliverius M, Kala Z, Campa D, Rizzato C, Canzian F, Pezzilli R, Talar-Wojnarowska R, Malecka-Panas E, Sperti C, Federico Zambon C, Pedrazzoli S, Fogar P, Milanetto AC, Capurso G, Delle Fave G, Valente R, Gazouli M, Malleo G, Teresa Lawlor R, Strobel O, Hackert T, Giese N, Vodicka P, Vodickova L, Landi S, Tavano F, Gioffreda D, Piepoli A, Pazienza V, Mambrini A, Pedata M, Cantore M, Bambi F, Ermini S, Funel N, Lemstrova R, and Soucek P

Subjects
Adult, Aged, Carcinoma, Pancreatic Ductal pathology, Enhancer Elements, Genetic genetics, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Pancreatic Neoplasms pathology, Prognosis, Risk Factors, Carcinoma, Pancreatic Ductal genetics, Genetic Predisposition to Disease genetics, Organic Cation Transport Proteins genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted.

Published
2017
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7. Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.

Author

Campa D, Capurso G, Pastore M, Talar-Wojnarowska R, Milanetto AC, Landoni L, Maiello E, Lawlor RT, Malecka-Panas E, Funel N, Gazouli M, De Bonis A, Klüter H, Rinzivillo M, Delle Fave G, Hackert T, Landi S, Bugert P, Bambi F, Archibugi L, Scarpa A, Katzke V, Dervenis C, Liço V, Furlanello S, Strobel O, Tavano F, Basso D, Kaaks R, Pasquali C, Gentiluomo M, Rizzato C, and Canzian F

Subjects
Aged, Alleles, Case-Control Studies, Computational Biology, Cyclin-Dependent Kinase Inhibitor p16, Female, Gene Silencing, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Homozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Statistical, Neuroendocrine Tumors diagnosis, Odds Ratio, Pancreatic Neoplasms diagnosis, Risk, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p18 genetics, Germ-Line Mutation, Neuroendocrine Tumors genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (OR hom  = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

Published
2016
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8. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk.

Author

Campa D, Pastore M, Gentiluomo M, Talar-Wojnarowska R, Kupcinskas J, Malecka-Panas E, Neoptolemos JP, Niesen W, Vodicka P, Delle Fave G, Bueno-de-Mesquita HB, Gazouli M, Pacetti P, Di Leo M, Ito H, Klüter H, Soucek P, Corbo V, Yamao K, Hosono S, Kaaks R, Vashist Y, Gioffreda D, Strobel O, Shimizu Y, Dijk F, Andriulli A, Ivanauskas A, Bugert P, Tavano F, Vodickova L, Zambon CF, Lovecek M, Landi S, Key TJ, Boggi U, Pezzilli R, Jamroziak K, Mohelnikova-Duchonova B, Mambrini A, Bambi F, Busch O, Pazienza V, Valente R, Theodoropoulos GE, Hackert T, Capurso G, Cavestro GM, Pasquali C, Basso D, Sperti C, Matsuo K, Büchler M, Khaw KT, Izbicki J, Costello E, Katzke V, Michalski C, Stepien A, Rizzato C, and Canzian F

Subjects
Alleles, Asian People, Binding Sites, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p16, DNA Methylation, Disease Progression, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, International Cooperation, Japan, Odds Ratio, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms ethnology, Prognosis, Retrospective Studies, White People, Carcinoma, Pancreatic Ductal genetics, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p18 genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk., Competing Interests: John P. Neoptolemos has the following conflicts of interest. Payment for Lectures: Amgen, Mylan Research Grants: Taiho Pharma (Japan); KAEL GemVax (Korea); AstraZeneca; Clovis Oncology and Ventana; Pharma Nord. Consultancy: Boehringer Ingelheim Pharma GmbH & Co. KG; Novartis Pharma AG; KAEL GemVax; Astellas. Educational Travel Grants: NUCANA. The other authors do not have any conflict of interest to declare.

Published
2016
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9. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer.

Author

Childs EJ, Mocci E, Campa D, Bracci PM, Gallinger S, Goggins M, Li D, Neale RE, Olson SH, Scelo G, Amundadottir LT, Bamlet WR, Bijlsma MF, Blackford A, Borges M, Brennan P, Brenner H, Bueno-de-Mesquita HB, Canzian F, Capurso G, Cavestro GM, Chaffee KG, Chanock SJ, Cleary SP, Cotterchio M, Foretova L, Fuchs C, Funel N, Gazouli M, Hassan M, Herman JM, Holcatova I, Holly EA, Hoover RN, Hung RJ, Janout V, Key TJ, Kupcinskas J, Kurtz RC, Landi S, Lu L, Malecka-Panas E, Mambrini A, Mohelnikova-Duchonova B, Neoptolemos JP, Oberg AL, Orlow I, Pasquali C, Pezzilli R, Rizzato C, Saldia A, Scarpa A, Stolzenberg-Solomon RZ, Strobel O, Tavano F, Vashist YK, Vodicka P, Wolpin BM, Yu H, Petersen GM, Risch HA, and Klein AP

Subjects
Aged, Australia, Europe, Female, Gene Frequency, Genetic Loci genetics, Genome-Wide Association Study methods, Genotype, Humans, Male, Middle Aged, North America, Risk Factors, Chromosomes, Human, Pair 17 genetics, Chromosomes, Human, Pair 2 genetics, Chromosomes, Human, Pair 3 genetics, Chromosomes, Human, Pair 7 genetics, Genetic Predisposition to Disease genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Published
2015
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10. The estimation of metaloproteinases and their inhibitors blood levels in patients with pancreatic tumors.

Author

Śmigielski J, Piskorz Ł, Talar-Wojnarowska R, Malecka-Panas E, Jabłoński S, and Brocki M

Subjects
Aged, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms pathology, Pancreatic Neoplasms surgery, Prognosis, Retrospective Studies, Biomarkers, Tumor blood, Matrix Metalloproteinase 2 blood, Matrix Metalloproteinase 9 blood, Pancreatic Neoplasms blood, Tissue Inhibitor of Metalloproteinase-1 blood, Tissue Inhibitor of Metalloproteinase-2 blood
Abstract

Background: The aim of the study was to evaluate the concentration of proteolytic enzymes, MMP-2 and MMP-9, and their tissue inhibitors, TIMP-1 and TIMP-2, in the blood of patients with benign and malignant pancreatic tumors., Methods: MMP-2, MMP-9, TIMP-1, and TIMP-2 were evaluated in the patients with benign and malignant pancreatic tumors before surgery and in the 30-day follow-up. The study covered 134 patients aged 54 to 76 years, who were divided into groups by TNM staging., Results: Before the operation, the highest mean concentration of MMP-2 was found in patients with unresectable cancer, whereas the highest level of MMP-9 was in patients with resectable cancer. The highest level of TIMP-1 was noted in patients with inflammatory tumors. In 1 month following the operation, the highest level of MMP-2 was also in patients with unresectable cancer and the highest level of TIMP-2 in patients with inflammatory tumors., Conclusions: The evaluation of the level of the studied cytokines in the pancreatic tumor patients can be diagnostically significant in the differentiation of benign and malignant changes. The changes in the levels of the studied enzymes and their inhibitors can have a prognostic value in the clinical severity of pancreatic cancer.

Published
2013
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11. Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic Disease ReseArch (PANDoRA) consortium.

Author

Campa D, Rizzato C, Capurso G, Giese N, Funel N, Greenhalf W, Soucek P, Gazouli M, Pezzilli R, Pasquali C, Talar-Wojnarowska R, Cantore M, Andriulli A, Scarpa A, Jamroziak K, Delle Fave G, Costello E, Khaw KT, Heller A, Key TJ, Theodoropoulos G, Malecka-Panas E, Mambrini A, Bambi F, Landi S, Pedrazzoli S, Bassi C, Pacetti P, Piepoli A, Tavano F, di Sebastiano P, Vodickova L, Basso D, Plebani M, Fogar P, Büchler MW, Bugert P, Vodicka P, Boggi U, Neoptolemos JP, Werner J, and Canzian F

Subjects
Adult, Aged, Aged, 80 and over, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Adenocarcinoma epidemiology, Adenocarcinoma genetics, Genetic Predisposition to Disease epidemiology, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics
Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the European Union and in the USA, but little is known about its genetic susceptibility. The PANcreatic Disease ReseArch (PANDoRA) consortium was established to unite the efforts of different research groups; its aim is to create a large bio-database to uncover new genetic factors for pancreatic cancer risk, response to treatment, and patient survival. So far 2220 cases of pancreatic adenocarcinoma, a smaller number of cases of endocrine pancreatic tumours (n=86), chronic pancreatitis (n=272) and 3847 healthy controls have been collected. As a collective effort of the consortium, SNPs associated with pancreatic adenocarcinoma risk from a genome-wide association study performed in Caucasians were replicated. The possibility that the same genetic polymorphisms may influence patient survival as well was also addressed. This collective effort is particularly important for pancreatic cancer because it is a relatively rare disease for which little is known about aetiopathogenesis and risk factors. The recruitment of additional collaborators and partner institutions is continuously on-going., (Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Published
2013
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12. Role of cyclooxygenase-2 gene polymorphisms in pancreatic carcinogenesis.

Author

Talar-Wojnarowska R, Gasiorowska A, Olakowski M, Lampe P, Smolarz B, Romanowicz-Makowska H, and Malecka-Panas E

Subjects
Adult, Aged, Aged, 80 and over, Female, Genotype, Humans, Male, Middle Aged, Cyclooxygenase 2 genetics, Genetic Predisposition to Disease, Pancreatic Neoplasms genetics, Polymorphism, Genetic
Abstract

Aim: To evaluate the clinical significance of -765G/C and -1195G/A cyclooxygenase-2 (COX-2) gene polymorphisms in patients with pancreatic cancer (PC)., Methods: The study included 201 patients: 85 with PC and 116 healthy controls. -765G/C and -1195G/A COX-2 gene polymorphisms were studied in DNA isolated from blood samples. The associations of the analyzed genotypes and clinical data at diagnosis were evaluated., Results: We found an increased frequency of the homozygous -1195AA COX-2 genotype in patients with PC (53.7%) compared with the control group (21%) (P < 0.01). In contrast, the distribution of genotype and allele frequencies of the -765G/C COX-2 polymorphism in the PC patients were not different from those in control groups. A correlation between presence of homozygous -1195AA COX-2 genotype and tumor size > 3 cm was observed (P < 0.05). Analyzed polymorphisms were unrelated to the patients' sex and age, nor to the presence of regional or distant metastases., Conclusion: These preliminary results indicate that the -1195G/A COX-2 polymorphism may play an important role in PC prognosis and carcinogenesis.

Published
2011
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13. Vascular endothelial growth factor (VEGF) genotype and serum concentration in patients with pancreatic adenocarcinoma and chronic pancreatitis.

Author

Talar-Wojnarowska R, Gasiorowska A, Olakowski M, Lekstan A, Lampe P, Smolarz B, Romanowicz-Makowska H, Kulig A, and Malecka-Panas E

Subjects
Adenocarcinoma blood, Adult, Aged, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Pancreatic Neoplasms blood, Pancreatitis, Chronic blood, Polymorphism, Genetic, Adenocarcinoma genetics, Pancreatic Neoplasms genetics, Pancreatitis, Chronic genetics, Vascular Endothelial Growth Factor A blood, Vascular Endothelial Growth Factor A genetics
Abstract

Vascular endothelial growth factor (VEGF) is necessary for microvasculature development and important for growth and spread of pancreatic tumors. Functional polymorphism of VEGF gene at position C-460T and G+405C may influence VEGF serum level. VEGF gene polymorphisms at position C-460T and G+405C were evaluated in 85 patients with pancreatic adenocarcinoma (PA), 72 - with chronic pancreatitis (CP) and 50 healthy volunteers. VEGF genotypes were studied in DNA isolated from blood samples and serum VEGF concentrations were measured. We found an increased frequency of the homozygous +405C/C VEGF genotype in patients with PA (55.3%) compared with CP (25%) and control group (16%; p<0.01). In contrast, the distribution of genotype and allele frequencies of the -460C/T polymorphism in the PA patients did not differ from those in CP and control groups. Serum levels of VEGF were significantly higher in PA patients (mean level: 441 ± 37.2 pg/ml) compared with CP patients (217 ± 13.6 pg/ml; p<0.001) and control group (137 ± 7.7 pg/ml; p<0.001). No relationship between VEGF serum levels and VEGF gene polymorphisms have been found. Our findings suggest that +405C/C VEGF genotype may contribute to pancreatic carcinogenesis. VEGF serum levels, although elevated in PA patients, are not associated with analysed VEGF polymorphisms.

Published
2010

14. Clinical value of serum neopterin, tissue polypeptide-specific antigen and CA19-9 levels in differential diagnosis between pancreatic cancer and chronic pancreatitis.

Author

Talar-Wojnarowska R, Gasiorowska A, Olakowski M, Lekstan A, Lampe P, and Malecka-Panas E

Subjects
Adenocarcinoma diagnosis, Adult, Aged, Aged, 80 and over, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms diagnosis, Pancreatitis, Chronic diagnosis, Predictive Value of Tests, ROC Curve, Young Adult, Adenocarcinoma blood, Biomarkers, Tumor blood, CA-19-9 Antigen blood, Neopterin blood, Pancreatic Neoplasms blood, Pancreatitis, Chronic blood, Peptides blood
Abstract

Background: Neopterin and tissue polypeptide-specific antigen (TPS) have been suggested to be useful in differential diagnosis between pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The aim of our study was to compare the clinical usefulness of CA19-9, neopterin and TPS serum levels in patients with PA and CP., Methods: The study included 85 patients with PA, 72 with CP and 50 healthy controls. The serum concentrations of neopterin, TPS and CA19-9 were measured (DRG International, USA). The associations of the analyzed markers and clinical data at diagnosis have been evaluated., Results: Serum levels of neopterin, TPS and CA19-9 were higher in PA patients compared to CP (p < 0.001). TPS and CA19-9 levels were also elevated in patients with CP compared to the control group (p < 0.001). In contrast, there was no difference between neopterin serum levels in CP patients and the control group (p > 0.05). Neopterin showed the best sensitivity and specificity (91.8 and 87.5%) in PA diagnosis compared to CA19-9 (respectively 83.5 and 75%) and TPS (75.3 and 65.3%)., Conclusion: Our results indicate that neopterin may be potentially useful in differential diagnosis between PA and CP. Assessment of TPS probably adds no significant information to that obtained with CA19-9 and neopterin. and IAP., (Copyright © 2011 S. Karger AG, Basel.)

Published
2010
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15. Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis.

Author

Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Kulig A, and Malecka-Panas E

Subjects
Adenocarcinoma blood, Adenocarcinoma secondary, Aged, Aged, 80 and over, Case-Control Studies, Female, Humans, Interleukin-6 blood, Liver Neoplasms secondary, Lymphatic Metastasis, Male, Middle Aged, Pancreas pathology, Pancreatic Neoplasms blood, Pancreatic Neoplasms pathology, Pancreatitis, Chronic blood, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Adenocarcinoma genetics, Interleukin-6 genetics, Pancreatic Neoplasms genetics, Pancreatitis, Chronic genetics
Abstract

The aim of our study was to assess the clinical significance of -174G/C Il-6 gene polymorphism and Il-6 serum level in patients with pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The study included 41 with pancreatic adenocarcinoma, 56 with chronic pancreatitis, and 50 healthy volunteers, hospitalized between 2003 and 2006. Il-6 serum levels were measured with an enzyme-linked immunoassay and Il-6 gene polymorphism was studied in DNA isolated from peripheral blood. In PA and CP patients Il-6 serum levels were significantly higher than in the control group (P < 0.01). The levels of Il-6 in the patients with tumor size >or=3.5 cm were higher than that in patients with smaller tumors (P < 0.01). The elevated Il-6 levels were also correlated with the presence of liver metastases (P < 0.01). Mean Il-6 serum level was significantly higher in patients homozygous G/G for -174 Il-6 gene compared with patients with at least one C allele. Our findings indicate that -174G/C Il-6 gene polymorphism influences circulating Il-6 levels. Increased Il-6 serum levels may be correlated with tumor size and the presence of liver metastases in patients with pancreatic adenocarcinoma.

Published
2009
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16. Tumor necrosis factor alpha and interferon gamma genes polymorphisms and serum levels in pancreatic adenocarcinoma.

Author

Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Kulig A, and Malecka-Panas E

Subjects
Adenocarcinoma blood, Adenocarcinoma complications, Aged, Aged, 80 and over, Cachexia blood, Cachexia genetics, Female, Genetic Predisposition to Disease, Humans, Interferon-gamma blood, Male, Middle Aged, Pancreatic Neoplasms blood, Pancreatic Neoplasms complications, Pancreatitis blood, Pancreatitis genetics, Polymerase Chain Reaction, Polymorphism, Restriction Fragment Length, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha blood, Adenocarcinoma genetics, Interferon-gamma genetics, Pancreatic Neoplasms genetics, Tumor Necrosis Factor-alpha genetics
Abstract

Several biochemical pathways can lead to cancer cachexia, one of which involves the elevation of the cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interferon gamma (INF-gamma). It was suggested that TNF-alpha and INF-gamma genes polymorphisms may influence these cytokines serum levels, but published data are still controversial. The aim of our study was to assess the clinical significance of -308G/A TNF-alpha and +874A/T INF-gamma genes polymorphisms as well as TNF-alpha and INF-gamma serum levels in pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP) as regards to healthy volunteers. We studied 41 patients with pancreatic adenocarcinoma, 56 with chronic pancreatitis and 50 healthy volunteers. Peripheral venous blood samples were obtained from all patients for TNF-alpha and INF-gamma serum concentrations measurement. After DNA isolation TNF-alpha and INF-gamma genes polymorphisms have been studied using restriction fragment length polymorphism (RFLP) analysis. Plasma levels of TNF-alpha were significantly higher in PA patients (32.7 pg/ml) compared with CP patients (3.2 pg/ ml) and control group (<1.6 pg/ml; p<0.01). Similarly, plasma levels of INF-gamma in PA patients (12.7 pg/ml) were higher from those in CP and control group (<7.1 pg/ml; p<0.01). In contrast, there were no differences between CP patients and healthy volunteers in INF-gamma levels. We observed a trend toward a correlation between weight loss in PA patients and TNF-alpha serum level (p=0.02). The TNF-alpha and INF-gamma genotype distribution were similar in patients with PA, CP and control group. We have not observed any association between TNF-alpha and INF-gamma serum levels and their genes polymorphisms. Our results suggest that elevated TNF-alpha serum level may have clinical significance in the development of cachexia in PA patients. -308G/A TNF-alpha and +874A/T INF-gamma genes polymorphisms probably do not play important role in pancreatic diseases. Key words: pancreatic adenocarcinoma, tumor necrosis factor alpha, interferon gamma, cytokines, polymorphism.

Published
2009
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17. Molecular pathogenesis of pancreatic adenocarcinoma: potential clinical implications.

Author

Talar-Wojnarowska R and Malecka-Panas E

Subjects
ErbB Receptors genetics, ErbB Receptors metabolism, Genes, Tumor Suppressor, Humans, Mutation, Oncogenes, Adenocarcinoma genetics, Adenocarcinoma therapy, Genetic Therapy, Pancreatic Neoplasms genetics, Pancreatic Neoplasms therapy
Abstract

Despite scientific efforts and significant progress in understanding the basic cellular event in pancreatic adenocarcinoma (PA), survival rates have not changed much during the last 20 years. Prognosis in pancreatic cancer remains unsatisfactory due to its late clinical presentation, low surgical resectability rates, and resistance to chemotherapy. Novel therapeutic strategies are needed in order to improve the prognosis of patients with PA. Improvement of our knowledge of the molecular biology of pancreatic cancer may have important clinical implications in pancreatic cancer risk assessment, early diagnosis, and management. In human pancreatic cancer, a specific sequence of oncogene and tumor suppressor gene alterations is observed, including K-ras, HER-2/neu, p16, p53, and DPC4. The prevalence of these genetic alterations rises with increasing severity of dysplasia of the ductal mucosal lesions. Drugs that target these molecular abnormalities hold great promise for PA treatment in the near future. The focus of this review is to evaluate the gene mutations in pancreatic cancer, with emphasis on those studies that are most important to the clinical practice. Our review also summarizes current aspects of PA treatment and the differential diagnosis of pancreatic cancer and chronic pancreatitis.

Published
2006

18. Comparative evaluation of p53 mutation in pancreatic adenocarcinoma and chronic pancreatitis.

Author

Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowskal H, Strzelczyk J, Janiak A, and Malecka-Panas E

Subjects
Aged, Chronic Disease, Female, Humans, Male, Middle Aged, Polymerase Chain Reaction, Polymorphism, Single-Stranded Conformational, Prevalence, Adenocarcinoma genetics, Diagnosis, Differential, Genes, p53, Mutation, Pancreatic Neoplasms genetics, Pancreatitis genetics, Tumor Suppressor Protein p53 genetics
Abstract

Background/aims: Pancreatic adenocarcinoma (PA) has a very poor prognosis. In patients suffering from chronic pancreatitis (CP) the risk for the PA development is higher than in the general population. The purpose of the study was to compare the prevalence of p53 mutations in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases., Methodology: We examined 49 patients who underwent Whipple resection or distal pancreatectomy for pancreatic adenocarcinoma (26 subjects) or chronic pancreatitis (23 subjects). DNA from pancreatic tissue was analyzed for p53 mutations with PCR/SSCP methods., Results: The p53 gene mutation has been shown in 16 (61.5%) of the PA patients (9 in exon 5 and 7 in exon 7) and in 2 (8.6%) of CP patients (1 in exon 5 and 1 in exon 8; p < 0.001). There was a significant correlation between p53 mutation and G3 tumor differentiation (p < 0.01). Overall median survival in patients with PA was 8.5 months. No relationship between presence of p53 mutation and survival time in PA patients has been observed., Conclusions: The specificity of p53 mutation for pancreatic cancer is very high. Our results indicate that p53 gene mutation may provide an additional tool in differential diagnosis of CP and PC.

Published
2006

19. Clinical significance of K-ras and c-erbB-2 mutations in pancreatic adenocarcinoma and chronic pancreatitis.

Author

Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Strzelczyk J, Janiak A, Kulig A, and Malecka-Panas E

Subjects
Adult, Aged, Cell Transformation, Neoplastic, DNA Mutational Analysis, DNA, Neoplasm analysis, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Pancreatectomy, Polymerase Chain Reaction, Adenocarcinoma diagnosis, Adenocarcinoma genetics, Genes, erbB-2 genetics, Genes, ras genetics, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms genetics, Pancreatitis diagnosis, Pancreatitis genetics
Abstract

Background: The differentiation of chronic pancreatitis (CP) from pancreatic adenocarcinoma (PA) remains the great challenge for clinicians. The purpose of this study was to compare the prevalence of K-ras and c-erbB-2 mutations in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases., Methods: The study included 49 patients who underwent Whipple resection or distal pancreatectomy for pancreatic adenocarcinoma (26 subjects) or chronic pancreatitis (23 subjects). DNA from pancreatic tissue was analyzed for K-ras codon 12 and c-erbB-2 mutations with PCR amplifications., Results: The K-ras gene mutation has been shown in 20 (76.9%) PA cases and in 8 (34.8%) CP cases (p<0.01). Prevalence of c-erbB-2 amplification in patients with PA was 17 (65.3%), which was not different from CP, 16 (56.5%) (p=0.58). There was a significant correlation between K-ras mutation and lymph node metastases (p=0.025) as well as between K-ras mutation and G3 tumor differentiation (p=0.037). Overall median survival in patients with PA was 9.5 mo. There was no relationship between presence of K-ras (p=0.58) or c-erbB-2 (p=0.17) mutation and survival time in PA patients., Conclusion: Those results may indicate that both K-ras and c-erbB-2 play a role in pancreatic carcinogenesis, however only K-ras may provide an additional tool in differential diagnosis of CP and PC.

Published
2005
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20. Usefulness of p16 and K-ras mutation in pancreatic adenocarcinoma and chronic pancreatitis differential diagnosis.

Author

Talar-Wojnarowska R, Gasiorowska A, Smolarz B, Romanowicz-Makowska H, Strzelczyk J, Janiak A, Kulig A, and Malecka-Panas E

Subjects
Adenocarcinoma diagnosis, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor genetics, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms diagnosis, Pancreatitis, Chronic diagnosis, Proto-Oncogene Proteins p21(ras), Adenocarcinoma genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Genes, p16 physiology, Genes, ras genetics, Mutation, Pancreatic Neoplasms genetics, Pancreatitis, Chronic genetics, Proto-Oncogene Proteins genetics, ras Proteins genetics
Abstract

Background: The differentiation of chronic pancreatitis (CP) from pancreatic adenocarcinoma (PA) remains a great challenge. The purpose of the study was to compare the prevalence of p16 and K-ras mutation in PA and CP in order to evaluate their usefulness in differential diagnosis of those diseases., Methods: The study included 44 patients who underwent Whipple resection or distal pancreatectomy for PA (23 subjects) or CP (21 subjects). DNA from pancreatic tissue was analysed for K-ras mutation (codon 12) and p16 mutations with PCR amplifications., Results: The K-ras gene mutation has been shown in 17 (73,9%) cases with pancreatic adenocarcinoma which was significantly more often than in chronic pancreatitis - 9 (42,8%) (p<0,01). Prevalence of p16 mutations in patients with PA was 18 (78,3%) and with CP - 7 (33,3%) (p<0,01). K-ras and p16 mutations together have been observed in 16 (69,6%) cases in patients with PC and only in 3 (14,3%) - with CP (p<0,01). No statistically significant association between K-ras or p16 mutations and tumor size, sex or patient age has been observed., Conclusion: It is suggested that simultaneous measurement of K-ras and p16 mutations may provide an additional tool in differential diagnosis of chronic pancreatitis and pancreatic adenocarcinoma.

Published
2004

21. Prognostic factors in the operative and palliative treatment of pancreatic cancer.

Author

Talar-Wojnarowska R, Gasiorowska A, Strzelczyk J, Janiak A, and Malecka-Panas E

Subjects
Adenocarcinoma diagnostic imaging, Adenocarcinoma mortality, Adenocarcinoma pathology, Adenocarcinoma surgery, Adenocarcinoma therapy, Adult, Aged, Aged, 80 and over, Carcinoma, Ductal diagnostic imaging, Carcinoma, Ductal mortality, Carcinoma, Ductal pathology, Carcinoma, Ductal surgery, Carcinoma, Ductal therapy, Duodenum surgery, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pancreatectomy mortality, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms mortality, Pancreatic Neoplasms pathology, Prognosis, Survival Analysis, Time Factors, Tomography, X-Ray Computed, Treatment Outcome, Palliative Care, Pancreatic Neoplasms surgery, Pancreatic Neoplasms therapy
Abstract

Recent studies have emphasized the importance of patient selection for the surgical resection of pancreatic adenocarcinoma based on reproducible prognostic factors. The aim of the study was to investigate the prognostic factors affecting long-term survival in patients with resectable and nonresectable pancreatic cancer and to evaluate their prognostic value. Forty six patients (25 women, 21 men, aged 44-80) with ductal adenocarcinoma of the pancreas were reviewed. Primary tumor size and regional enlargement of lymph nodes was assessed with enhanced CT scan. 13 patients were treated conservatively, 9 with standard Whipple procedure (pancreatoduodenectomy) and 24 - with palliative surgery. Survival probabilities were computed using univariate Kaplan-Meier analysis. Log-rank test was used to compare survival between groups. Overall median survival was 6 months with a 4 years survival of 2.2%. There was no difference in survival time (ST) between patients aged 65 years or younger and older (p=0.71). MeanST in patients after Whipple procedure was 10.3, after palliative surgery - 9.4 and after conservative treatment - 4.4 months (p<0.05). Thirty-day surgical mortality was 9.4%. ST was significantly longer in patients with tumors 3 cm or less of diameter compared with larger ones (p<0.05). Presenting signs and symptoms, like jaundice, diabetes, alkaline phosphatase, aspartate and alanine aminotransferase elevation and history of cholecystectomy did not have any significant impact on survival. The only significant independent factors improving survival were: operative treatment and tumor size smaller than 3 cm.

Published
2003

22. Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma

Author

Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., Canzian, F., Obazee, O., Archibugi, L., Andriulli, A., Soucek, P., Malecka-Panas, E., Ivanauskas, A., Johnson, T., Gazouli, M., Pausch, T., Lawlor, R. T., Cavestro, G. M., Milanetto, A. C., Di Leo, M., Pasquali, C., Hegyi, P., Szentesi, A., Radu, C. E., Gheorghe, C., Theodoropoulos, G. E., Bergmann, F., Brenner, H., Vodickova, L., Katzke, V., Campa, D., Strobel, O., Kaiser, J., Pezzilli, R., Federici, F., Mohelnikova-Duchonova, B., Boggi, U., Lemstrova, R., Johansen, J. S., Bojesen, S. E., Chen, I., Jensen, B. V., Capurso, G., Pazienza, V., Dervenis, C., Sperti, C., Mambrini, A., Hackert, T., Kaaks, R., Basso, D., Talar-Wojnarowska, R., Maiello, E., Izbicki, J. R., Cuk, K., Saum, K. U., Cantore, M., Kupcinskas, J., Palmieri, O., Delle Fave, G., Landi, S., Salvia, R., Fogar, P., Vashist, Y. K., Scarpa, A., Vodicka, P., Tjaden, C., Iskierka-Jazdzewska, E., and Canzian, F.

Subjects
Male, Cancer Research, pancreatic cancer, Genes, BRCA2, I157T, Polymorphism, Single Nucleotide, Humans, Genetic Predisposition to Disease, Germ-Line Mutation, Aged, BRCA2 Protein, K3326X, PANDoRA consortium, rs11571833, rs17879961, Oncology, Pancreatic cancer, Middle Aged, Pancreatic Neoplasms, Checkpoint Kinase 2, Case-Control Studies, Female, Carcinoma, Pancreatic Ductal
Abstract

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Published
2018

23. EU Pancreas: An Integrated European Platform for Pancreas Cancer Research - from Basic Science to Clinical and Public Health Interventions for a Rare Disease

Author

Milne, R., La Vecchia, C., Van Steen, K., Hahn, S., Buchholz, M., Costello, E., Esposito, I., Hoheisel, J. D., Lange, B., Lopez-Bigas, N., Michalski, C. W., Real, F. X., Brand, A., Malats, N., LaVecchia, C., Macic, D., Ceric, T., Iovanna, J., Kleeff, J., Gazouli, M., Dervenis, C., Hegyi, P., Ruhl, R., Shafat, A., Sharp, L., Rayan, A., DeCarli, A., Tortora, G., Sileikis, A., Barauskas, G., Eriksson Steigen, S., Ikdahl, T., Malecka-Panas, E., Silva, F. S., Barbu, T. S., Popescu, I., Durisova, M., Majekova, M., Dolzan, V., Genc, L., Yildirim, H., Crnogorac-Jurcevic, T., Bulchholz, M., Greenhalf, B., Campbell, F., Kloeppel, G., De Mesquita, B. B., Hoheisel, J., Brazma, A., Herwig, R., Van Cutsum, E., Goldstein, D., Birney, E., Bassi, C., Biankin, A., Scarpa, A., Michalski, C., Dufresne, M., Chelala, C., Kocher, H., Steyerberg, E., Cecconi, D., Löhr, M., Gutierrez- Ibarluzea, I., Adany, R., Horgan, D., Taruscio, D., Wolff-Boehnisch, B., Dauben, H. -P., Barbardorttir, R. B., Papadopoulos, I., Callens, P., Holcatova, I., Brenner, H., Campa, D., Canzian, F., Rizzato, C., Lüttges, J., Gress, T., Bartch, D., Vlahou, T., Fillat, C., Bayés, M., Gut, I., Gut, M., Gasull, M., Barberá, V., Porta, M., Molero, X., Duell, E., Ález-Couto, E., Carrato, A., Guillén, C., Martinelli, P., Hidalgo, M., Heeschen, C., Valencia, A., Calle, M. L., Guigó, R., Scelo, G., Boffetta, P., Maisonneuve, P., Bosetti, C., Lucenteforte, E., Jeurnink, S., Van Duijnhoven, F., Zatonski, W., Petronijevic, L., Verbeke, C., Neoptolemos, J., Institute for Public Health Genomics, Health Services Research, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Milne, R., La Vecchia, C., Van Steen, K., Hahn, S., Buchholz, M., Costello, E., Esposito, I., Hoheisel, J.D., Lange, B., Lopez-Bigas, N., Michalski, C.W., Real, F.X., Brand, A., Malats, N., LaVecchia, C., Macic, D., Ceric, T., Iovanna, J., Kleeff, J., Gazouli, M., Dervenis, C., Hegyi, P., Ruhl, R., Shafat, A., Sharp, L., Rayan, A., DeCarli, A., Tortora, G., Sileikis, A., Barauskas, G., Eriksson Steigen, S., Ikdahl, T., Malecka-Panas, E., Silva, F.S., Barbu, T.S., Popescu, I., Durisova, M., Majekova, M., Dolzan, V., Genc, L., Yildirim, H., Crnogorac-Jurcevic, T., Bulchholz, M., Greenhalf, B., Campbell, F., Kloeppel, G., De Mesquita, B.B., Hoheisel, J., Brazma, A., Herwig, R., Van Cutsum, E., Goldstein, D., Birney, E., Bassi, C., Biankin, A., Scarpa, A., Michalski, C., Dufresne, M., Chelala, C., Kocher, H., Steyerberg, E., Cecconi, D., Löhr, M., Gutierrez- Ibarluzea, I., Adany, R., Horgan, D., Taruscio, D., Wolff-Boehnisch, B., Dauben, H.-P., Barbardorttir, R.B., Papadopoulos, I., Callens, P., Holcatova, I., Brenner, H., Campa, D., Canzian, F., Rizzato, C., Lüttges, J., Gress, T., Bartch, D., Vlahou, T., Fillat, C., Bayés, M., Gut, I., Gut, M., Gasull, M., Barberá, V., Porta, M., Molero, X., Duell, E., Ález-Couto, E., Carrato, A., Guillén, C., Martinelli, P., Hidalgo, M., Heeschen, C., Valencia, A., Calle, M.L., Guigó, R., Scelo, G., Boffetta, P., Maisonneuve, P., Bosetti, C., Lucenteforte, E., Jeurnink, S., Van Duijnhoven, F., Zatonski, W., Petronijevic, L., Verbeke, C., and Neoptolemos, J.

Subjects
Biomedical Research, Omics data, International Cooperation, Best practice, Information Dissemination, COST Action BM1204, Context (language use), Translational Research, Biomedical, Rare Diseases, Multidisciplinary approach, Neoplasms, Pancrea, Humans, Medicine, Precision Medicine, Mortality, Pancreas cancer, Genetics (clinical), Public health, Rare disease, Training and mobility, Data integration, Early-stage researchers, Harmonization, Health management system, business.industry, Research, Pancreatic Neoplasm, Public Health, Environmental and Occupational Health, Precision medicine, Research Personnel, ddc, Europe, Pancreatic Neoplasms, Practice Guideline, Action (philosophy), Health, Cancer research, Public Health, Personalized medicine, Therapeutic, business
Abstract

Background: Large-scale international collaboration is essential to decipher relevant information in the context of omics-scale interrogations in cancer research. This is even more important for rare and fatal diseases like pancreas cancer (PC). Methods: The COST Action BM1204 is a unique platform to facilitate the collaboration of a broad range of European and international PC multidisciplinary research groups in order to: (1) integrate knowledge and experience in a multidisciplinary way ‘from cell to society', (2) promote the application of uniform study tools and protocols, (3) foster their optimal use by early-stage researchers, (4) enhance the mobility and training of researchers, and (5) disseminate the results produced to the broader society. Results: This Action will develop novel interdisciplinary tools for collaborative research to improve our understanding of PC and its prevention, diagnosis and treatment. It also aims to answer questions related to the etiology, early detection, evidence-based and personalized treatment, and health management for PC. Furthermore, the Action will contribute to new insights into PC personalized medicine and beyond as well as to the understanding of complex and rare diseases taking PC as a best practice example. The Action aims at attracting young scholars across a range of disciplines in collaboration with more experienced researchers and enhancing active European participation in the international scenario of PC research. Conclusion: The ultimate aim is to foster PC research in Europe and to coordinate this effort with other international initiatives to reduce disease mortality.

Published
2013
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24. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author

Campa, D, Pastore, M, Capurso, G, Hackert, T, Di Leo, M, Izbicki, JR, Khaw, K-T, Gioffreda, D, Kupcinskas, J, Pasquali, C, Macinga, P, Kaaks, R, Stigliano, S, Peeters, PH, Key, TJ, Talar-Wojnarowska, R, Vodicka, P, Valente, R, Vashist, YK, Salvia, R, Papaconstantinou, I, Shimizu, Y, Valsuani, C, Zambon, CF, Gazouli, M, Valantiene, I, Niesen, W, Mohelnikova-Duchonova, B, Hara, K, Soucek, P, Malecka-Panas, E, Bueno-de-Mesquita, HBA, Johnson, T, Brenner, H, Tavano, F, Fogar, P, Ito, H, Sperti, C, Butterbach, K, Latiano, A, Andriulli, A, Cavestro, GM, Busch, ORC, Dijk, F, Greenhalf, W, Matsuo, K, Lombardo, C, Strobel, O, König, A-K, Cuk, K, Strothmann, H, Katzke, V, Cantore, M, Mambrini, A, Oliverius, M, Pezzilli, R, Landi, S, Canzian, F, Other departments, CCA - Imaging and biomarkers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, Daniele, Pastore, Manuela, Capurso, Gabriele, Hackert, Thilo, Di Leo, Milena, Izbicki, Jakob R, Khaw, Kay tee, Gioffreda, Domenica, Kupcinskas, Juoza, Pasquali, Claudio, Macinga, Peter, Kaaks, Rudolf, Stigliano, Serena, Peeters, Petra H, Key, Timothy J, Talar wojnarowska, Renata, Vodicka, Pavel, Valente, Roberto, Vashist, Yogesh K, Salvia, Roberto, Papaconstantinou, Ioanni, Shimizu, Yasuhiro, Valsuani, Chiara, Zambon, Carlo Federico, Gazouli, Maria, Valantiene, Irena, Niesen, Willem, Mohelnikova duchonova, Beatrice, Hara, Kazuo, Soucek, Pavel, Malecka panas, Ewa, Bueno de mesquita, H. Ba, Johnson, Theron, Brenner, Herman, Tavano, Francesca, Fogar, Paola, Ito, Hidemi, Sperti, Cosimo, Butterbach, Katja, Latiano, Anna, Andriulli, Angelo, Cavestro, GIULIA MARTINA, Busch, Olivier R. C, Dijk, Frederike, Greenhalf, William, Matsuo, Keitaro, Lombardo, Carlo, Strobel, Oliver, König, Anna katharina, Cuk, Katarina, Strothmann, Hendrik, Katzke, Verena, Cantore, Maurizio, Mambrini, Andrea, Oliverius, Martin, Pezzilli, Raffaele, Landi, Stefano, and Canzian, Federico

Subjects
Adult, Male, Cancer Research, endocrine system diseases, Chronic pancreatiti, pancreatic ductal adenocarcinoma, Adenocarcinoma, Polymorphism, Single Nucleotide, genetic polymorphisms, Risk Factors, Pancreatitis, Chronic, Biomarkers, Tumor, genetic polymorphism, Humans, Trypsin, Chronic, Polymorphism, Aged, Retrospective Studies, Tumor, Carcinoma, association, Nuclear Proteins, Single Nucleotide, Middle Aged, ACUTE PANCREATITIS, Prognosis, digestive system diseases, PANCREATIC CANCER, Pancreatic Neoplasms, Pancreatitis, Oncology, Pancreatic Ductal, Case-Control Studies, Chronic pancreatitis, Carcinoma, Pancreatic Ductal, Female, Follow-Up Studies, Trypsinogen, Biomarkers
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639 rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous =1.19, 95% CI 1.02-1.38, p=0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous =0.51, 95% CI 0.39-0.67, p=1.10x10(-6) ) and MORC4-rs 12837024 (ORhomozygous =2.07 (1.55-2.77, ptrend =0.7x10(-11) ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639 rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. This article is protected by copyright. All rights reserved.

Published
2017

25. Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk

Author

Raffaele Pezzilli, Pavel Vodicka, Andrea Párniczky, George Theodoropoulos, Renata Talar-Wojnarowska, Paolo Giorgio Arcidiacono, Ugo Boggi, Bálint Erőss, Ewa Małecka-Panas, Martin Oliverius, Daniele Campa, Rita T. Lawlor, Faik G. Uzunoglu, Maria Chiara Petrone, Livia Archibugi, Stefania Bunduc, Edita Kreivenaite, Beatrice Mohelnikova-Duchonova, Manuel Gentiluomo, Maria Liliana Piredda, Giulia Peduzzi, Thilo Hackert, Francesco Perri, Giuseppe Vanella, Olivier R. Busch, Hermann Brenner, Pavel Soucek, John P. Neoptolemos, Martin Schneider, Sabrina Gloria Giulia Testoni, Luca Morelli, Krzysztof Jamroziak, Federico Canzian, Daniela Basso, Silvia Carrara, Maria Gazouli, Juozas Kupcinskas, Konstantinos Georgiou, Xīn Gào, Claudio Pasquali, Cosimo Sperti, Evaristo Maiello, Vytautas Kiudelis, Mara Götz, Martin Loos, Gabriele Capurso, Francesca Bazzocchi, Martin Lovecek, Bas Bueno-de-Mesquita, Viktor Hlavac, Niccola Funel, Roel Vermeulen, Maarten F. Bijlsma, Anna Caterina Milanetto, Ye Lu, Giulia Martina Cavestro, Stefano Ermini, Andrea Szentesi, Jakob R. Izbicki, William Greenhalf, Francesca Tavano, Feng Guo, Marta Puzzono, Domenica Gioffreda, Péter Hegyi, Eithne Costello, Casper H.J. van Eijck, Stefano Landi, Peduzzi, G., Gentiluomo, M., Tavano, F., Arcidiacono, P. G., Ermini, S., Vodicka, P., Boggi, U., Cavestro, G. M., Capurso, G., Morelli, L., Milanetto, A. C., Pezzilli, R., Lawlor, R. T., Carrara, S., Lovecek, M., Soucek, P., Guo, F., Hackert, T., Uzunoglu, F. G., Gazouli, M., Parniczky, A., Kupcinskas, J., Bijlsma, M. F., Bueno-De-Mesquita, B., Vermeulen, R., van Eijck, C. H. J., Jamroziak, K., Talar-Wojnarowska, R., Greenhalf, W., Gioffreda, D., Petrone, M. C., Landi, S., Archibugi, L., Puzzono, M., Funel, N., Sperti, C., Piredda, M. L., Mohelnikova-Duchonova, B., Lu, Y., Hlavac, V., Gao, X., Schneider, M., Izbicki, J. R., Theodoropoulos, G., Bunduc, S., Kreivenaite, E., Busch, O. R., Malecka-Panas, E., Costello, E., Perri, F., Giulia Testoni, S. G., Vanella, G., Pasquali, C., Oliverius, M., Brenner, H., Loos, M., Gotz, M., Georgiou, K., Eross, B., Maiello, E., Szentesi, A., Bazzocchi, F., Basso, D., Neoptolemos, J. P., Hegyi, P., Kiudelis, V., Canzian, F., Campa, D., Surgery, CCA - Cancer biology and immunology, CCA - Imaging and biomarkers, Center of Experimental and Molecular Medicine, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism

Subjects
Mitochondrial DNA, Pancreatic ductal adenocarcinoma, Nuclear gene, endocrine system diseases, Epidemiology, Biology, SUSCEPTIBILITY, Polymorphism, Single Nucleotide, SDG 3 - Good Health and Well-being, Pancreatic cancer, medicine, Humans, 03.02. Klinikai orvostan, Genetic variability, Carcinoma, Pancreatic Ductal, Case-Control Studies, Genetic Variation, Genome, Mitochondrial, Mitochondria, Pancreatic Neoplasms, Polymorphism, GENOME-WIDE ASSOCIATION, Gene, Genetics, Genome, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY, Carcinoma, Single Nucleotide, Metabolism, medicine.disease, digestive system diseases, Mitochondrial, Oncology, Pancreatic Ductal
Abstract

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10−5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Published
2021

26. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility

Author

Ewa Małecka-Panas, Jakob R. Izbicki, Krzysztof Jamroziak, Claudio Pasquali, Sabrina Gloria Giulia Testoni, Silvia Carrara, Livia Archibugi, Domenica Gioffreda, Francesca Tavano, Matteo Giaccherini, Gregorio Di Franco, Niccolò Napoli, Viktor Hlavac, Yogesh K. Vashist, Oliver Strobel, Martin Lovecek, Paolo Giorgio Arcidiacono, Thilo Hackert, Klara Cervena, Stefano Landi, Claudio Luchini, Andrea Szentesi, Maria Gazouli, Giulia Martina Cavestro, Daniele Campa, Gabriele Capurso, Rita T. Lawlor, Martin Oliverius, Edita Kreivenaite, Audrius Ivanauskas, Luca Morelli, Raffaele Pezzilli, Maria Chiara Petrone, Chiara Corradi, Stefania Moz, George Theodoropoulos, Michael F. Nentwich, Pavel Vodicka, Giuseppe Vanella, Hermann Brenner, Manuel Gentiluomo, John P. Neoptolemos, Cosimo Sperti, Angelo Andriulli, Ye Lu, Péter Hegyi, Cristian Gheorghe, Anna Caterina Milanetto, Pavel Soucek, László Gajdán, Erika Darvasi, Juozas Kupcinskas, Federico Canzian, Raffaella Alessia Zuppardo, Corradi, C., Gentiluomo, M., Gajdan, L., Cavestro, G. M., Kreivenaite, E., Di Franco, G., Sperti, C., Giaccherini, M., Petrone, M. C., Tavano, F., Gioffreda, D., Morelli, L., Soucek, P., Andriulli, A., Izbicki, J. R., Napoli, N., Malecka-Panas, E., Hegyi, P., Neoptolemos, J. P., Landi, S., Vashist, Y., Pasquali, C., Lu, Y., Cervena, K., Theodoropoulos, G. E., Moz, S., Capurso, G., Strobel, O., Carrara, S., Hackert, T., Hlavac, V., Archibugi, L., Oliverius, M., Vanella, G., Vodicka, P., Arcidiacono, P. G., Pezzilli, R., Milanetto, A. C., Lawlor, R. T., Ivanauskas, A., Szentesi, A., Kupcinskas, J., Testoni, S. G. G., Lovecek, M., Nentwich, M., Gazouli, M., Luchini, C., Zuppardo, R. A., Darvasi, E., Brenner, H., Gheorghe, C., Jamroziak, K., Canzian, F., and Campa, D.

Subjects
Male, Cancer Research, association study, long noncoding RNA, pancreatic cancer, single nucleotide polymorphism, Aged, Carcinoma, Pancreatic Ductal, Case-Control Studies, Computational Biology, Cyclin-Dependent Kinase Inhibitor p15, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, MicroRNAs, Middle Aged, Pancreatic Neoplasms, RNA, Long Noncoding, Polymorphism, Single Nucleotide, Single-nucleotide polymorphism, Locus (genetics), Genome-wide association study, Biology, Genome, 03 medical and health sciences, 0302 clinical medicine, SNP, Genetic variability, Polymorphism, Gene, Genetics, Carcinoma, Single Nucleotide, Long non-coding RNA, Oncology, Pancreatic Ductal, 030220 oncology & carcinogenesis, RNA, Long Noncoding
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second cancer-related cause of death by 2030. Identifying novel risk factors, including genetic risk loci, could be instrumental in risk stratification and implementation of prevention strategies. Long noncoding RNAs (lncRNAs) are involved in regulation of key biological processes, and the possible role of their genetic variability has been unexplored so far. Combining genome wide association studies and functional data, we investigated the genetic variability in all lncRNAs. We analyzed 9893 PDAC cases and 9969 controls and identified a genome-wide significant association between the rs7046076 SNP and risk of developing PDAC (P = 9.73 × 10-9 ). This SNP is located in the NONHSAG053086.2 (lnc-SMC2-1) gene and the risk allele is predicted to disrupt the binding of the lncRNA with the micro-RNA (miRNA) hsa-mir-1256 that regulates several genes involved in cell cycle, such as CDKN2B. The CDKN2B region is pleiotropic and its genetic variants have been associated with several human diseases, possibly though an imperfect interaction between lncRNA and miRNA. We present a novel PDAC risk locus, supported by a genome-wide statistical significance and a plausible biological mechanism.

Published
2021

27. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Author

John P. Neoptolemos, Markus W. Büchler, Jakob R. Izbicki, Ben Schöttker, Cosmeri Rizzato, Cornelia Schroeder, Salvatore Paiella, Hanneke W. M. van Laarhoven, William Greenhalf, Simona Bursi, Renata Talar-Wojnarowska, Christos Dervenis, Ludmila Vodickova, Francesca Tavano, Giulia Martina Cavestro, Thilo Hackert, Claudio Pasquali, Ewa Małecka-Panas, Gabriele Capurso, Andrea Mambrini, Daniele Campa, Andrea Padoan, Ioannis S. Papanikolaou, Raffaele Pezzilli, Péter Hegyi, Beatrice Mohelnikova-Duchonova, Federica Gemignani, Michael F. Nentwich, Pavel Vodicka, Stefano Landi, Richárd Szmola, Anna Caterina Milanetto, Eithne Costello, Rudolf Kaaks, Laura Ginocchi, Bernd Holleczek, Erika Darvasi, Verena Katzke, Evaristo Maiello, Manuel Gentiluomo, Ondrej Strouhal, Orazio Palmieri, Juozas Kupcinskas, Alice Alessandra Galeotti, Viktor Hlavac, George Theodoropoulos, Audrius Ivanauskas, Maria Gazouli, Ferenc Izbéki, Federico Canzian, Oliver Strobel, Ofure Obazee, Martin Lovecek, Timothy J. Key, Domenica Gioffreda, Pavel Soucek, Ugo Boggi, Krzysztof Jamroziak, Cosimo Sperti, Maarten F. Bijlsma, Yogesh K. Vashist, Andrea Szentesi, Hermann Brenner, Livia Archibugi, Giuseppe Vanella, Daniela Basso, Radiotherapy, Center of Experimental and Molecular Medicine, CCA - Cancer Treatment and Quality of Life, Oncology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Galeotti, A. A., Gentiluomo, M., Rizzato, C., Obazee, O., Neoptolemos, J. P., Pasquali, C., Nentwich, M., Cavestro, G. M., Pezzilli, R., Greenhalf, W., Holleczek, B., Schroeder, C., Schottker, B., Ivanauskas, A., Ginocchi, L., Key, T. J., Hegyi, P., Archibugi, L., Darvasi, E., Basso, D., Sperti, C., Bijlsma, M. F., Palmieri, O., Hlavac, V., Talar-Wojnarowska, R., Mohelnikova-Duchonova, B., Hackert, T., Vashist, Y., Strouhal, O., Van Laarhoven, H., Tavano, F., Lovecek, M., Dervenis, C., Izbeki, F., Padoan, A., Malecka-Panas, E., Maiello, E., Vanella, G., Capurso, G., Izbicki, J. R., Theodoropoulos, G. E., Jamroziak, K., Katzke, V., Kaaks, R., Mambrini, A., Papanikolaou, I. S., Szmola, R., Szentesi, A., Kupcinskas, J., Bursi, S., Costello, E., Boggi, U., Milanetto, A. C., Landi, S., Gazouli, M., Vodickova, L., Soucek, P., Gioffreda, D., Gemignani, F., Brenner, H., Strobel, O., Buchler, M., Vodicka, P., Paiella, S., Canzian, F., and Campa, D.

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Multifactorial Inheritance, Pancreatic disease, genetic epidemiology, Population, Single-nucleotide polymorphism, Disease, pancreas and biliary tract, Polymorphism, Single Nucleotide, Risk Assessment, ABO Blood-Group System, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Pancreatic cancer, Internal medicine, Genetics, medicine, oncology, Humans, education, Genetics (clinical), Alleles, Early Detection of Cancer, Genetic association, education.field_of_study, business.industry, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Genetic epidemiology, 030220 oncology & carcinogenesis, Cohort, Female, business, Carcinoma, Pancreatic Ductal
Abstract

BackgroundMost cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection.ObjectiveWe generated a polygenic risk score (PRS) for PDAC risk prediction, combining the effect of known risk SNPs, and carried out an exploratory analysis of a multifactorial score.MethodsWe tested the associations of the individual known risk SNPs on up to 2851 PDAC cases and 4810 controls of European origin from the PANcreatic Disease ReseArch (PANDoRA) consortium. Thirty risk SNPs were included in a PRS, which was computed on the subset of subjects that had 100% call rate, consisting of 839 cases and 2040 controls in PANDoRA and 6420 cases and 4889 controls from the previously published Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case-Control Consortium genome-wide association studies. Additional exploratory multifactorial scores were constructed by complementing the genetic score with smoking and diabetes.ResultsThe scores were associated with increased PDAC risk and reached high statistical significance (OR=2.70, 95% CI 1.99 to 3.68, p=2.54×10−10 highest vs lowest quintile of the weighted PRS, and OR=14.37, 95% CI 5.57 to 37.09, p=3.64×10−8, highest vs lowest quintile of the weighted multifactorial score).ConclusionWe found a highly significant association between a PRS and PDAC risk, which explains more than individual SNPs and is a step forward in the direction of the construction of a tool for risk stratification in the population.

Published
2020

28. Genome-wide association study identifies an early onset pancreatic cancer risk locus

Author

Verena Katzke, Jakob R. Izbicki, Francesca Tavano, Rita T. Lawlor, Thilo Hackert, Raffaella Alessia Zuppardo, Giulia Martina Cavestro, Federico Canzian, Frederike Dijk, Martin Oliverius, George Theodoropoulos, Pavel Soucek, Manuel Gentiluomo, Rudolf Kaaks, Erika Darvasi, Yogesh K. Vashist, Bill Greenhalf, Juozas Kupcinskas, Maurizio Lucchesi, Borislav Rusev, Andrea Szentesi, Gabriele Capurso, Ewa Małecka-Panas, Lucia Moletta, Beatrice Mohelnikova-Duchonova, Franco Bambi, Ugo Boggi, Alba Ballerini, Krzysztof Jamroziak, Ben Schöttker, Simona Bursi, Raffaele Pezzilli, Gyula Farkas, Dania Bozzato, Áron Vincze, Stefano Landi, Anna Caterina Milanetto, Péter Hegyi, Michael F. Nentwich, Laura Ginocchi, Pavel Vodicka, Stefania Moz, Ludmila Vodickova, Hermann Brenner, Olivier R. Busch, Viktor Hlavac, Audrius Ivanauskas, John P. Neoptolemos, Domenica Gioffreda, Ofure Obazee, Livia Archibugi, Nathalia A. Giese, Giuseppe Vanella, Xin Gao, Renata Talar-Wojnarowska, Angelo Andriulli, Oliver Strobel, Daniele Campa, Maria Gazouli, Pathology, CCA - Cancer biology and immunology, Surgery, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Re-generation and cancer of the digestive system, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, D., Gentiluomo, M., Obazee, O., Ballerini, A., Vodickova, L., Hegyi, P., Soucek, P., Brenner, H., Milanetto, A. C., Landi, S., Gao, X., Bozzato, D., Capurso, G., Tavano, F., Vashist, Y., Hackert, T., Bambi, F., Bursi, S., Oliverius, M., Gioffreda, D., Schottker, B., Ivanauskas, A., Mohelnikova-Duchonova, B., Darvasi, E., Pezzilli, R., Malecka-Panas, E., Strobel, O., Gazouli, M., Katzke, V., Szentesi, A., Cavestro, G. M., Farkas, G., Izbicki, J. R., Moz, S., Archibugi, L., Hlavac, V., Vincze, A., Talar-Wojnarowska, R., Rusev, B., Kupcinskas, J., Greenhalf, B., Dijk, F., Giese, N., Boggi, U., Andriulli, A., Busch, O. R., Vanella, G., Vodicka, P., Nentwich, M., Lawlor, R. T., Theodoropoulos, G. E., Jamroziak, K., Zuppardo, R. A., Moletta, L., Ginocchi, L., Kaaks, R., Neoptolemos, J. P., Lucchesi, M., and Canzian, F.

Subjects
Oncology, Male, Cancer Research, medicine.medical_specialty, Pancreatic disease, pancreatic cancer, early onset, Single-nucleotide polymorphism, Genome-wide association study, very early onset pancreatic cancer, Polymorphism, Single Nucleotide, 03 medical and health sciences, single nucleotide polymorphisms, 0302 clinical medicine, Risk Factors, Pancreatic cancer, Internal medicine, Genetic predisposition, Medicine, Humans, Genetic Predisposition to Disease, Genetic variability, Pancreas, Genetic association, genome-wide association study, business.industry, Middle Aged, medicine.disease, Pancreatic Neoplasms, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Age of onset, business, Carcinoma, Pancreatic Ductal
Abstract

Early onset pancreatic cancer (EOPC) is a rare disease with a very high mortality rate. Almost nothing is known on the genetic susceptibility of EOPC, therefore we performed a genome-wide association study (GWAS) to identify novel genetic variants specific for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) at younger ages. In the first phase, conducted on 821 cases with age of onset ≤60 years, of whom 198 with age of onset ≤50, and 3227 controls from PanScan I-II, we observed four SNPs (rs7155613, rs2328991, rs4891017 and rs12610094) showing an association with EOPC risk (P < 1x10-4 ). We replicated these SNPs in the PANcreatic Disease ReseArch (PANDoRA) consortium and used additional in silico data from PanScan III and PanC4. Among these four variants rs2328991 was significant in an independent set of 855 cases with age of onset ≤60 years, of whom 265 with age of onset≤50, and 4142 controls from the PANDoRA consortium while in the in silico data we observed no statistically significant association. However, the resulting meta-analysis supported the association (P = 1.15x10-4 ). In conclusion we propose a novel variant rs2328991 to be involved in EOPC risk. Even though it was not possible to find a mechanistic link between the variant and the function, the association is supported by a solid statistical significance obtained in the largest study on EOPC genetics present so far in the literature. This article is protected by copyright. All rights reserved.

Published
2020

29. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer

Author

Herbert Yu, Gabriele Capurso, Robert N. Hoover, Beatrice Mohelnikova-Duchonova, Amanda L. Blackford, Harvey A. Risch, H. Bas Bueno-de-Mesquita, Timothy J. Key, Stephen J. Chanock, Ann L. Oberg, Federico Canzian, Lingeng Lu, Maria Gazouli, Michelle Cotterchio, Daniele Campa, John P. Neoptolemos, Claudio Pasquali, Rachel E. Neale, Rayjean J. Hung, William R. Bamlet, Raffaele Pezzilli, Stefano Landi, Juozas Kupcinskas, Joseph M. Herman, Erica J. Childs, Ivana Holcatova, Steven Gallinger, Manal M. Hassan, Ewa Małecka-Panas, Pavel Vodicka, Donghui Li, Maarten F. Bijlsma, Irene Orlow, Lenka Foretova, Robert C. Kurtz, Yogesh K. Vashist, Francesca Tavano, Evelina Mocci, Amethyst Saldia, Michael Borges, Sean P. Cleary, Gloria M. Petersen, Brian M. Wolpin, Sara H. Olson, Kari G. Chaffee, Aldo Scarpa, Vladimir Janout, Elizabeth A. Holly, Niccola Funel, Hermann Brenner, Ghislaine Scelo, Laufey T. Amundadottir, Rachael Z. Stolzenberg-Solomon, Paige M. Bracci, Charles S. Fuchs, Paul Brennan, Oliver Strobel, Michael Goggins, Giulia Martina Cavestro, Cosmeri Rizzato, Andrea Mambrini, Alison P. Klein, CCA -Cancer Center Amsterdam, Radiotherapy, Childs, Ej, Mocci, E, Campa, D, Bracci, Pm, Gallinger, S, Goggins, M, Li, D, Neale, Re, Olson, Sh, Scelo, G, Amundadottir, Lt, Bamlet, Wr, Bijlsma, Mf, Blackford, A, Borges, M, Brennan, P, Brenner, H, Bueno de Mesquita, Hb, Canzian, F, Capurso, G, Cavestro, GIULIA MARTINA, Chaffee, Kg, Chanock, Sj, Cleary, Sp, Cotterchio, M, Foretova, L, Fuchs, C, Funel, N, Gazouli, M, Hassan, M, Herman, Jm, Holcatova, I, Holly, Ea, Hoover, Rn, Hung, Rj, Janout, V, Key, Tj, Kupcinskas, J, Kurtz, Rc, Landi, S, Lu, L, Malecka Panas, E, Mambrini, A, Mohelnikova Duchonova, B, Neoptolemos, Jp, Oberg, Al, Orlow, I, Pasquali, C, Pezzilli, R, Rizzato, C, Saldia, A, Scarpa, A, Stolzenberg Solomon, Rz, Strobel, O, Tavano, F, Vashist, Yk, Vodicka, P, Wolpin, Bm, Yu, H, Petersen, Gm, Risch, Ha, and Klein, A. P.

Subjects
Male, pancreatic cancer, Genome-wide association study, Gastroenterology, Aged, Australia, Chromosomes, Human, Pair 17, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 7, Europe, Female, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, North America, Pancreatic Neoplasms, Risk Factors, Polymorphism, Single Nucleotide, Genetics, Medicine (all), 0302 clinical medicine, CDKN2A, 0303 health sciences, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, Pair 3, Pair 2, Pair 7, Human, medicine.medical_specialty, PALB2, Biology, Article, Chromosomes, 03 medical and health sciences, Internal medicine, ABO blood group system, Pancreatic cancer, medicine, Polymorphism, 030304 developmental biology, Pair 17, Odds ratio, medicine.disease, Confidence interval, pancreatic cancer, genome-wide association study
Abstract

Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

Published
2015
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30. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

Author

Ugo Boggi, Cosmeri Rizzato, Krzysztof Jamroziak, Andrea Mambrini, Gabriele Capurso, Yogesh K. Vashist, Valerio Pazienza, Christoph W. Michalski, Giulia Martina Cavestro, Keitaro Matsuo, Ewa Małecka-Panas, Jakob R. Izbicki, Harald Klüter, Timothy J. Key, Ludmila Vodickova, Vincenzo Corbo, Kenji Yamao, Domenica Gioffreda, Anna Stępień, Milena Di Leo, Willem Niesen, Audrius Ivanauskas, Cosimo Sperti, Carlo Federico Zambon, Peter Bugert, Beatrice Mohelnikova-Duchonova, Satoyo Hosono, Angelo Andriulli, Renata Talar-Wojnarowska, Maria Gazouli, John P. Neoptolemos, Franco Bambi, Francesca Tavano, Claudio Pasquali, Yasuhiro Shimizu, Manuela Pastore, Federico Canzian, Rudolf Kaaks, Daniele Campa, Gianfranco Delle Fave, Frederike Dijk, George Theodoropoulos, Raffaele Pezzilli, Paola Pacetti, Eithne Costello, Pavel Vodicka, Verena Katzke, Stefano Landi, Juozas Kupcinskas, Oliver Strobel, Martin Lovecek, Thilo Hackert, Manuel Gentiluomo, Markus W. Büchler, Pavel Soucek, Roberto Valente, Bas Bueno-de-Mesquita, Hidemi Ito, Kay-Tee Khaw, Olivier R. Busch, Daniela Basso, Campa, D, Pastore, M, Gentiluomo, M, Talar Wojnarowska, R, Kupcinskas, J, Malecka Panas, E, Neoptolemos, Jp, Niesen, W, Vodicka, P, Delle Fave, G, Bas Bueno de Mesquita, H, Gazouli, M, Pacetti, P, Di Leo, M, Ito, H, Klüter, H, Soucek, P, Corbo, V, Yamao, K, Hosono, S, Kaaks, R, Vashist, Y, Gioffreda, D, Strobel, O, Shimizu, Y, Dijk, F, Andriulli, A, Ivanauskas, A, Bugert, P, Tavano, F, Vodickova, L, Zambon, Cf, Lovecek, M, Landi, S, Key, Tj, Boggi, U, Pezzilli, R, Jamroziak, K, Mohelnikova Duchonova, B, Mambrini, A, Bambi, F, Busch, O, Pazienza, V, Valente, R, Theodoropoulos, G, Hackert, T, Capurso, G, Cavestro, GIULIA MARTINA, Pasquali, C, Basso, D, Sperti, C, Matsuo, K, Büchler, M, Khaw, Kt, Izbicki, J, Costello, E, Katzke, V, Michalski, C, Stepien, A, Rizzato, C, Canzian, F., CCA -Cancer Center Amsterdam, Pathology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Surgery

Subjects
0301 basic medicine, Pancreatic disease, CDKN2A, association study, miRSNP, pancreatic cancer, single nucleotide polymorphisms, Alleles, Asian Continental Ancestry Group, Binding Sites, Carcinoma, Pancreatic Ductal, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p18, DNA Methylation, Disease Progression, European Continental Ancestry Group, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, International Cooperation, Japan, Odds Ratio, Pancreatic Neoplasms, Prognosis, Retrospective Studies, Polymorphism, Single Nucleotide, Bioinformatics, 0302 clinical medicine, Medicine, Single Nucleotide, 3. Good health, Oncology, Pancreatic Ductal, 030220 oncology & carcinogenesis, Research Paper, Single-nucleotide polymorphism, White People, 03 medical and health sciences, Germline mutation, Asian People, Pancreatic cancer, Allele, Polymorphism, Cyclin-Dependent Kinase Inhibitor p16, business.industry, Carcinoma, Cancer, medicine.disease, 030104 developmental biology, Cancer research, business
Abstract

The CDKN2A(p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (OR het=1.14, 95% CI 1.01-1.27, p=0.026, ORhom =1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/Blocus could represent a genetic link between diabetes and pancreatic cancer risk.

Published
2016

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