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18 results on '"Tavano, Francesca"'

1. Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

Author

Gálvez-Montosa F, Peduzzi G, Sanchez-Maldonado JM, Ter Horst R, Cabrera-Serrano AJ, Gentiluomo M, Macauda A, Luque N, Ünal P, García-Verdejo FJ, Li Y, López López JA, Stein A, Bueno-de-Mesquita HB, Arcidiacono PG, Zanette DL, Kahlert C, Perri F, Soucek P, Talar-Wojnarowska R, Theodoropoulos GE, Izbicki JR, Tamás H, Van Laarhoven H, Nappo G, Petrone MC, Lovecek M, Vermeulen RCH, Adamonis K, Reyes-Zurita FJ, Holleczek B, Sumskiene J, Mohelníková-Duchoňová B, Lawlor RT, Pezzilli R, Aoki MN, Pasquali C, Petrenkiene V, Basso D, Bunduc S, Comandatore A, Brenner H, Ermini S, Vanella G, Goetz MR, Archibugi L, Lucchesi M, Uzunoglu FG, Busch O, Milanetto AC, Puzzono M, Kupcinskas J, Morelli L, Sperti C, Carrara S, Capurso G, van Eijck CHJ, Oliverius M, Roth S, Tavano F, Kaaks R, Szentesi A, Vodickova L, Luchini C, Schöttker B, Landi S, Dohan O, Tacelli M, Greenhalf W, Gazouli M, Neoptolemos JP, Cavestro GM, Boggi U, Latiano A, Hegyi P, Ginocchi L, Netea MG, Sánchez-Rovira P, Canzian F, Campa D, and Sainz J

Subjects
Humans, Transcription Factors genetics, White People genetics, Hepatocyte Nuclear Factor 3-alpha genetics, Hepatocyte Nuclear Factor 3-alpha metabolism, Case-Control Studies, Cohort Studies, Forkhead Transcription Factors, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Genetic Predisposition to Disease, Autophagy genetics, Polymorphism, Single Nucleotide, Tumor Suppressor Proteins genetics, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Biomarkers, Tumor genetics
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID rs9604789 variant with an increased risk of developing the disease (OR Meta  = 1.31, p = 9.67 × 10 -6 ). We also confirmed the association of TP63 rs1515496 and TP63 rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10 -8 and OR = 1.16, p = 2.74 × 10 -5 ). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63 rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10 -4 and p = 1.56 × 10 -3 ), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10 -4 ). These results were in agreement with research suggesting that the TP63 rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Published
2025
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2. Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

Author

Corradi C, Lencioni G, Felici A, Rizzato C, Gentiluomo M, Ermini S, Archibugi L, Mickevicius A, Lucchesi M, Malecka-Wojciesko E, Basso D, Arcidiacono PG, Petrone MC, Carrara S, Götz M, Bunduc S, Holleczek B, Aoki MN, Uzunoglu FG, Zanette DL, Mambrini A, Jamroziak K, Oliverius M, Lovecek M, Cavestro GM, Milanetto AC, Peduzzi G, Duchonova BM, Izbicki JR, Zalinkevicius R, Hlavac V, van Eijck CHJ, Brenner H, Vanella G, Vokacova K, Soucek P, Tavano F, Perri F, Capurso G, Hussein T, Kiudelis M, Kupcinskas J, Busch OR, Morelli L, Theodoropoulos GE, Testoni SGG, Adamonis K, Neoptolemos JP, Gazouli M, Pasquali C, Kormos Z, Skalicky P, Pezzilli R, Sperti C, Kauffmann E, Büchler MW, Schöttker B, Hegyi P, Capretti G, Lawlor RT, Canzian F, and Campa D

Subjects
Humans, Male, Case-Control Studies, White People genetics, Female, Quantitative Trait Loci, Alleles, Asian People genetics, Middle Aged, Polymorphism, Single Nucleotide, Pancreatic Neoplasms genetics, Genetic Predisposition to Disease, DNA Methylation, Carcinoma, Pancreatic Ductal genetics, GPI-Linked Proteins genetics, Linkage Disequilibrium, Antigens, Neoplasm genetics, Neoplasm Proteins genetics
Abstract

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10 -5 ). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association., (© 2024 UICC.)

Published
2024
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3. Genome-wide scan of long noncoding RNA single nucleotide polymorphisms and pancreatic cancer susceptibility.

Author

Corradi C, Gentiluomo M, Gajdán L, Cavestro GM, Kreivenaite E, Di Franco G, Sperti C, Giaccherini M, Petrone MC, Tavano F, Gioffreda D, Morelli L, Soucek P, Andriulli A, Izbicki JR, Napoli N, Małecka-Panas E, Hegyi P, Neoptolemos JP, Landi S, Vashist Y, Pasquali C, Lu Y, Cervena K, Theodoropoulos GE, Moz S, Capurso G, Strobel O, Carrara S, Hackert T, Hlavac V, Archibugi L, Oliverius M, Vanella G, Vodicka P, Arcidiacono PG, Pezzilli R, Milanetto AC, Lawlor RT, Ivanauskas A, Szentesi A, Kupcinskas J, Testoni SGG, Lovecek M, Nentwich M, Gazouli M, Luchini C, Zuppardo RA, Darvasi E, Brenner H, Gheorghe C, Jamroziak K, Canzian F, and Campa D

Subjects
Aged, Case-Control Studies, Computational Biology methods, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Carcinoma, Pancreatic Ductal genetics, Cyclin-Dependent Kinase Inhibitor p15 genetics, MicroRNAs genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide, RNA, Long Noncoding genetics
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., (© 2021 UICC.)

Published
2021
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4. Genetic polymorphisms associated with telomere length and risk of developing myeloproliferative neoplasms.

Author

Giaccherini M, Macauda A, Sgherza N, Sainz J, Gemignani F, Maldonado JMS, Jurado M, Tavano F, Mazur G, Jerez A, Góra-Tybor J, Gołos A, Mohedo FH, Lopez JM, Várkonyi J, Spadano R, Butrym A, Canzian F, and Campa D

Subjects
Aged, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Myeloproliferative Disorders etiology, Risk Factors, Myeloproliferative Disorders genetics, Polymorphism, Single Nucleotide, Telomere Homeostasis
Abstract

Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the "teloscore" in 480 MPN patients and 909 healthy controls in a European multi-center case-control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24-2.68, P = 2.21 × 10 -3 , comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (OR allelic  = 1.43; 95% CI 1.15-1.77; P = 1.35 × 10 -3 ). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development.

Published
2020
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5. Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients.

Author

Gentiluomo M, Puchalt García P, Galeotti AA, Talar-Wojnarowska R, Tjaden C, Tavano F, Strobel O, Kupcinskas J, Neoptolemos J, Hegyi P, Costello E, Pezzilli R, Sperti C, Lawlor RT, Capurso G, Szentesi A, Soucek P, Vodicka P, Lovecek M, Hackert T, Cavestro GM, Milanetto AC, Canzian F, and Campa D

Subjects
Aged, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal therapy, Case-Control Studies, Combined Modality Therapy, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Genotype, Humans, Male, Middle Aged, Multidrug Resistance-Associated Protein 2, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms therapy, Prognosis, Survival Rate, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal mortality, Multidrug Resistance-Associated Proteins genetics, Pancreatic Neoplasms mortality, Polymorphism, Single Nucleotide
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2019
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6. 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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7. 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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8. Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer.

Author

Barontini J, Antinucci M, Tofanelli S, Cammalleri M, Dal Monte M, Gemignani F, Vodicka P, Marangoni R, Vodickova L, Kupcinskas J, Vymetalkova V, Forsti A, Canzian F, Stein A, Moreno V, Mastrodonato N, Tavano F, Panza A, Barale R, Landi S, and Campa D

Subjects
Aged, Case-Control Studies, Czech Republic, Female, Genetic Association Studies, Humans, Italy, Lithuania, Male, Middle Aged, Spain, Taste Receptors, Type 2, Colonic Neoplasms genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Receptors, G-Protein-Coupled genetics, Rectal Neoplasms genetics
Abstract

Background: Genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut., Methods: We performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries., Results: We did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (P trend of = 0.0071)., Conclusions: Our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts.

Published
2017
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9. 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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10. 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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11. 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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12. 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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13. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility

Author

Campa, Daniele, Rizzato, Cosmeri, Stolzenberg Solomon, Rachael, Pacetti, Paola, Vodicka, Pavel, Cleary, Sean P, Capurso, Gabriele, Bueno de Mesquita, H. B. As, Werner, Jens, Gazouli, Maria, Butterbach, Katja, Ivanauskas, Audrius, Giese, Nathalia, Petersen, Gloria M, Fogar, Paola, Wang, Zhaoming, Bassi, Claudio, Ryska, Miroslav, Theodoropoulos, George E, Kooperberg, Charles, Donghui, Li, Greenhalf, William, Pasquali, Claudio, Hackert, Thilo, Fuchs, Charles S, Mohelnikova Duchonova, Beatrice, Sperti, Cosimo, Funel, Niccola, Dieffenbach, Aida Karina, Wareham, Nicholas J, Buring, Julie, Holcátová, Ivana, Costello, Eithne, Zambon, Carlo Federico, Kupcinskas, Juozas, Risch, Harvey A, Kraft, Peter, Bracci, Paige M, Pezzilli, Raffaele, Olson, Sara H, Sesso, Howard D, Hartge, Patricia, Strobel, Oliver, Małecka Panas, Ewa, Visvanathan, Kala, Arslan, Alan A, Pedrazzoli, Sergio, Souček, Pavel, Gioffreda, Domenica, Key, Timothy J, Talar Wojnarowska, Renata, Scarpa, Aldo, Mambrini, Andrea, Jacobs, Eric J, Jamroziak, Krzysztof, Klein, Alison, Tavano, Francesca, Bambi, Franco, Landi, Stefano, Austin, Melissa A, Vodickova, Ludmila, Brenner, Hermann, Chanock, Stephen J, Delle Fave, Gianfranco, Piepoli, Ada, Cantore, Maurizio, Zheng, Wei, Wolpin, Brian M, Amundadottir, Laufey T, and Canzian, Federico

Subjects
Adult, Male, Cancer Research, Adolescent, pancreatic cancer, telomerase, Polymorphism, Single Nucleotide, Article, Linkage Disequilibrium, susceptibility, Young Adult, 80 and over, Humans, Genetic Predisposition to Disease, Polymorphism, Aged, Aged, 80 and over, Medicine(all), Carcinoma, Single Nucleotide, Middle Aged, Pancreatic Neoplasms, Oncology, Pancreatic Ductal, Case-Control Studies, Mutation, polymorphisms, Carcinoma, Pancreatic Ductal, Female, Telomerase
Abstract

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio=0.85; 95% confidence interval=0.80-0.90, p=8.3 × 10-8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2=0.07, D′=0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p=3.0 × 10-5), rs4583925 (p=4.0 × 10-5) and rs2735948 (p=5.0 × 10-5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants. What's new? Most pancreatic cancer patients do not survive long after diagnosis, and, so far, there are not many genetic markers to help screen for the disease. In search of genetic predictors of pancreatic cancer, the authors zoomed in on a region linked to susceptibility to the disease. They measured the frequency of different variants of two genes, telomerase reverse transcriptase and telomerase RNA component, among thousands of pancreatic cancer patients and controls. They identified several variants of the TERT gene that indicate a boosted pancreatic cancer risk, and which may develop into useful prognostic tools.

Published
2015

14. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Klein, Alison P, Wolpin, Brian M, Risch, Harvey A, Stolzenberg-Solomon, Rachael Z, Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J, Hoskins, Jason W, Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetrius, Andreotti, Gabriella, Arslan, Alan A, Babic, Ana, Bamlet, William R, Beane-Freeman, Laura, Berndt, Sonja I, Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M, Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-De-Mesquita, Bas, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G, Chung, Charles C, Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J, Foretova, Lenka, Fuchs, Charles, Funel, Niccola, Gallinger, Steven, M Gaziano, J Michael, Gazouli, Maria, Giles, Graham G, Giovannucci, Edward, Goggins, Michael, Goodman, Gary E, Goodman, Phyllis J, Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J, Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A, Hoover, Robert, Hung, Rayjean J, Jacobs, Eric J, Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Kooperberg, Charles, Kulke, Matthew H, Kupcinskas, Juozas, Kurtz, Robert J, Laheru, Daniel, Landi, Stefano, Lawlor, Rita T, Lee, I-Min, LeMarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Mohelníková-Duchoňová, Beatrice, Neale, Rachel E, Neoptolemos, John P, Oberg, Ann L, Olson, Sara H, Orlow, Irene, Pasquali, Claudio, Patel, Alpa V, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X, Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D, Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P, Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D, Tobias, Geoffrey S, Van Den Eeden, Stephen K, Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicolas, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M, and Amundadottir, Laufey T

Subjects
Intracellular Signaling Peptides and Proteins, Proteins, Polymorphism, Single Nucleotide, 3. Good health, Pancreatic Neoplasms, Repressor Proteins, Hepatocyte Nuclear Factor 4, Tensins, Databases, Genetic, Humans, Intercellular Signaling Peptides and Proteins, Genetic Predisposition to Disease, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta
Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

15. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane-Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetrius, Andreotti, Gabriella, Brais, Lauren, Bueno-De-Mesquita, H Bas, Basso, Daniela, Berndt, Sonja I, Boutron-Ruault, Marie-Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka-Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Klein, Eric A, Kogevinas, Manolis, Krogh, Vittorio, Kupcinskas, Juozas, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra HM, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao-Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka-Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrios, Vashist, Yogesh, Vodicka, Pavel, Wactawski-Wende, Jean, Wentzensen, Nicolas, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Kooperberg, Charles, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charles, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg-Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, and Amundadottir, Laufey T

Subjects
Genotype, NR5A2, pancreatic cancer, Datasets as Topic, imputation, Polymorphism, Single Nucleotide, 3. Good health, Pancreatic Neoplasms, fine-mapping, Chromosomes, Human, Pair 1, GWAS, Chromosomes, Human, Pair 5, Humans, Genetic Predisposition to Disease, Chromosomes, Human, Pair 8, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

16. 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

17. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, Ej, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, Cc, Hautman, C, Arslan, Aa, Beane Freeman, L, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Giles, Gg, Goodman, Ge, Goodman, Pj, Kamineni, A, Kolonel, Ln, Kulke, Mh, Malats, N, Olson, Sh, Sesso, Hd, Visvanathan, K, White, E, Zheng, W, Abnet, Cc, Albanes, D, Andreotti, G, Brais, L, Bueno de Mesquita, Hb, Basso, D, Berndt, Si, Boutron Ruault, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, Jm, Gazouli, M, Giovannucci, El, Goggins, M, Gross, M, Haiman, Ca, Hassan, M, Helzlsouer, Kj, Hu, N, Hunter, Dj, Iskierka Jazdzewska, E, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Klein, Ea, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, Rc, Landi, Mt, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, Rl, Neale, Re, Oberg, Al, Panico, S, Patel, Av, Peeters, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Kooperberg, C, Risch, Ha, Jacobs, Ej, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, Sj, Petersen, Gm, Stolzenberg Solomon, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.

Subjects
0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract

Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10 −4 -2.0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

18. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Christopher A. Haiman, Herbert Yu, Lauren K. Brais, Gabriele Capurso, Eric J. Duell, Michelle Cotterchio, Núria Malats, Beatrice Mohelníková-Duchoňová, Claudio Pasquali, Gary E. Goodman, Giulia Martina Cavestro, Kala Visvanathan, Sean P. Cleary, Jill P. Smith, Jean Wactawski-Wende, Rita T. Lawlor, Gianluca Severi, J. Michael Gaziano, Kathy J. Helzlsouer, Charles C. Chung, Harvey A. Risch, Stephen K. Van Den Eeden, Elizabeth A. Holly, Bas Bueno-de-Mesquita, Patricia Hartge, Fei Chen, Mark D. Thornquist, Hermann Brenner, Ulrike Peters, Ghislaine Scelo, Steven Gallinger, Sonja I. Berndt, Howard D. Sesso, Lenka Foretova, Laufey T. Amundadottir, Mingfeng Zhang, Federico Canzian, Rudolf Kaaks, Stephen J. Chanock, Nicolas Wentzensen, Ann L. Oberg, Eric J. Jacobs, Peter Kraft, Rayjean J. Hung, Evelina Mocci, Maria Gazouli, Francesca Tavano, Michael Borges, Zhaoming Wang, Alan A. Arslan, Wei Zheng, Ayelet Borgida, Paige M. Bracci, Jason W. Hoskins, William R. Bamlet, Juozas Kupcinskas, Joseph M. Herman, Demetrius Albanes, Charles S. Fuchs, Nathaniel Rothman, Niccola Funel, Pavel Soucek, Edward Giovannucci, Paul Brennan, Thilo Hackert, Jun Zhong, Manolis Kogevinas, Robert N. Hoover, Michael Goggins, Amanda L. Blackford, Robert J. Kurtz, Malin Sund, Roger L. Milne, Stefano Landi, Francisco X. Real, Emily White, Miquel Porta, Ivana Holcatova, Kari G. Chaffee, Vladimir Janout, Charles Kooperberg, Péter Hegyi, Frederike Dijk, Yogesh K. Vashist, Andrea Mambrini, Matthew H. Kulke, I. Min Lee, Kai Yu, Alison P. Klein, Phyllis J. Goodman, Donghui Li, Julie E. Buring, Debra T. Silverman, Ana Babic, John P. Neoptolemos, Erica J. Childs, Alpa V. Patel, Sara H. Olson, Brian M. Wolpin, Krzysztof Jamroziak, Gloria M. Petersen, Xiao-Ou Shu, Renata Talar-Wojnarowska, Rachel E. Neale, Daniel A. Laheru, Kay-Tee Khaw, Eric A. Klein, Ashley Jermusyk, Graham G. Giles, Daniele Campa, Laura Beane-Freeman, Rachael Z. Stolzenberg-Solomon, Raffaele Pezzilli, Geoffrey S. Tobias, Pavel Vodicka, Irene Orlow, Anne Zeleniuch-Jacquotte, Ofure Obazee, Satu Männistö, Lingeng Lu, Manal Hasan, Loic LeMarchand, Gabriella Andreotti, CCA - Cancer biology and immunology, Pathology, Lung Cancer Research Foundation, Sol Goldman Pancreas Cancer Research Center, Geoffrey Beene Foundation, Arnold and Arlene Goldstein Family Foundation, National Health and Medical Research Council (Australia), Czech Science Foundation, Joan Rombauer Pancreatic Cancer Foundation, NIH - National Cancer Institute (NCI) (Estados Unidos), Instituto de Salud Carlos III, Ministerio de Ciencia y Tecnología (España), Red Temática de Investigación Cooperativa en Cáncer (España), Centro de Investigación Biomédica en Red - CIBERESP (Epidemiología y Salud Pública), Mocci, Evelina [0000-0002-7101-9556], Canzian, Federico [0000-0002-4261-4583], Chaffee, Kari G [0000-0002-7313-1875], Dijk, Frederike [0000-0003-3970-6601], Gazouli, Maria [0000-0002-3295-6811], Jacobs, Eric J [0000-0002-8458-7659], Klein, Eric A [0000-0002-1783-0698], Lu, Lingeng [0000-0001-9871-0809], Malats, Núria [0000-0003-2538-3784], Milne, Roger L [0000-0001-5764-7268], Neoptolemos, John P [0000-0002-6201-7399], Oberg, Ann L [0000-0003-2539-9807], Pezzilli, Raffaele [0000-0001-9827-7451], Porta, Miquel [0000-0003-1684-7428], Real, Francisco X [0000-0001-9501-498X], Sund, Malin [0000-0002-7516-9543], Tobias, Geoffrey S [0000-0002-2878-8253], Van Den Eeden, Stephen K [0000-0002-5599-8387], Yu, Herbert [0000-0003-3950-4815], Zheng, Wei [0000-0003-1226-070X], Obazee, Ofure [0000-0001-8791-5008], Amundadottir, Laufey T [0000-0003-1859-8971], Apollo - University of Cambridge Repository, Klein, Alison P., Wolpin, Brian M., Risch, Harvey A., Stolzenberg-Solomon, Rachael Z., Mocci, Evelina, Zhang, Mingfeng, Canzian, Federico, Childs, Erica J., Hoskins, Jason W., Jermusyk, Ashley, Zhong, Jun, Chen, Fei, Albanes, Demetriu, Andreotti, Gabriella, Arslan, Alan A., Babic, Ana, Bamlet, William R., Beane-Freeman, Laura, Berndt, Sonja I., Blackford, Amanda, Borges, Michael, Borgida, Ayelet, Bracci, Paige M., Brais, Lauren, Brennan, Paul, Brenner, Hermann, Bueno-De-Mesquita, Ba, Buring, Julie, Campa, Daniele, Capurso, Gabriele, Cavestro, Giulia Martina, Chaffee, Kari G., Chung, Charles C., Cleary, Sean, Cotterchio, Michelle, Dijk, Frederike, Duell, Eric J., Foretova, Lenka, Fuchs, Charle, Funel, Niccola, Gallinger, Steven, Gaziano, J. Michael M., Gazouli, Maria, Giles, Graham G., Giovannucci, Edward, Goggins, Michael, Goodman, Gary E., Goodman, Phyllis J., Hackert, Thilo, Haiman, Christopher, Hartge, Patricia, Hasan, Manal, Hegyi, Peter, Helzlsouer, Kathy J., Herman, Joseph, Holcatova, Ivana, Holly, Elizabeth A., Hoover, Robert, Hung, Rayjean J., Jacobs, Eric J., Jamroziak, Krzysztof, Janout, Vladimir, Kaaks, Rudolf, Khaw, Kay-Tee, Klein, Eric A., Kogevinas, Manoli, Kooperberg, Charle, Kulke, Matthew H., Kupcinskas, Juoza, Kurtz, Robert J., Laheru, Daniel, Landi, Stefano, Lawlor, Rita T., Lee, I. -Min, Lemarchand, Loic, Lu, Lingeng, Malats, Núria, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L., Mohelníková-Duchoňová, Beatrice, Neale, Rachel E., Neoptolemos, John P., Oberg, Ann L., Olson, Sara H., Orlow, Irene, Pasquali, Claudio, Patel, Alpa V., Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Real, Francisco X., Rothman, Nathaniel, Scelo, Ghislaine, Sesso, Howard D., Severi, Gianluca, Shu, Xiao-Ou, Silverman, Debra, Smith, Jill P., Soucek, Pavel, Sund, Malin, Talar-Wojnarowska, Renata, Tavano, Francesca, Thornquist, Mark D., Tobias, Geoffrey S., Van Den Eeden, Stephen K., Vashist, Yogesh, Visvanathan, Kala, Vodicka, Pavel, Wactawski-Wende, Jean, Wang, Zhaoming, Wentzensen, Nicola, White, Emily, Yu, Herbert, Yu, Kai, Zeleniuch-Jacquotte, Anne, Zheng, Wei, Kraft, Peter, Li, Donghui, Chanock, Stephen, Obazee, Ofure, Petersen, Gloria M., and Amundadottir, Laufey T.

Subjects
0301 basic medicine, Oncology, Genetics and Molecular Biology (all), Pancreatic disease, Chemistry(all), General Physics and Astronomy, Genome-wide association study, Disease, Biochemistry, DISEASE, Tensins, Databases, Genetic, IMPUTATION, 03.02. Klinikai orvostan, lcsh:Science, Càncer, Pancreas cancer, GENE-EXPRESSION, Cancer, RISK, Multidisciplinary, Chemistry (all), Pancreatic Neoplasm, Intracellular Signaling Peptides and Proteins, HNF1B, 3. Good health, TRANSCRIPTION FACTORS, Hepatocyte Nuclear Factor 4, Intercellular Signaling Peptides and Proteins, Human, Carcinoma, Pancreatic Ductal, medicine.medical_specialty, Science, Physics and Astronomy(all), Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), Cancer epidemiology, Pancreatic cancer, Internal medicine, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Allele, Càncer de pàncrees, Hepatocyte Nuclear Factor 1-beta, Cancer och onkologi, Biochemistry, Genetics and Molecular Biology (all), business.industry, Biochemistry, Genetics and Molecular Biology(all), Protein, Proteins, ADENOCARCINOMA, General Chemistry, Repressor Protein, medicine.disease, Pancreatic Neoplasms, Repressor Proteins, BODY-MASS INDEX, 030104 developmental biology, Tensin, Cancer and Oncology, Expression quantitative trait loci, lcsh:Q, business, ASSOCIATION ANALYSES, Genetics and Molecular Biology(all), Genome-Wide Association Study
Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10−8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10−14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10−10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10−8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10−8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene., Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.

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