Genome-wide association study identifies an early onset pancreatic cancer risk locus
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, metaanalýza, práce podpořená grantem
PubMed
32270874
DOI
10.1002/ijc.33004
Knihovny.cz E-zdroje
- Klíčová slova
- early onset, genome-wide association study, pancreatic cancer, single nucleotide polymorphisms, very early onset pancreatic cancer,
- MeSH
- celogenomová asociační studie metody MeSH
- duktální karcinom slinivky břišní genetika patologie MeSH
- genetická predispozice k nemoci genetika MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory slinivky břišní genetika patologie MeSH
- pankreas patologie MeSH
- rizikové faktory MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
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 < 1 × 10-4 ). 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 = 1.15 × 10-4 ). 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.
1st Department of Medicine University of Szeged Szeged Hungary
ARC Net Research Centre University and Hospital Trust of Verona Verona Italy
Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic
Biomedical Centre Faculty of Medicine in Pilsen Charles University Prague Pilsen Czech Republic
Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Florence Italy
Department of Biology University of Pisa Pisa Italy
Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland
Department of DIMED University of Padova Padova Italy
Department of DISCOG University of Padova Padova Italy
Department of Hematology Institute of Hematology and Transfusion Medicine Warsaw Poland
Department of Pathology Amsterdam UMC University of Amsterdam Amsterdam The Netherlands
Department of Surgery University of Szeged Szeged Hungary
Department of Toxicogenomics National Institute of Public Health Prague Czech Republic
Digestive and Liver Disease Unit S Andrea Hospital University Sapienza Rome Italy
Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany
Division of General and Transplant Surgery Pisa University Hospital Pisa Italy
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Institute for Translational Medicine Medical School University of Pécs Pécs Hungary
Laboratory of Biology Medical School National and Kapodistrian University of Athens Athens Greece
Molecular and Clinical Cancer Medicine Royal Liverpool University Hospital Liverpool UK
Pancreas Unit Department of Gastroenterology Polyclinic of Sant'Orsola Bologna Italy
Zobrazit více v PubMed
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394-424.
Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913-2921.
Maisonneuve P, Lowenfels AB. Risk factors for pancreatic cancer: a summary review of meta-analytical studies. Int J Epidemiol. 2015;44:186-198.
Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41:986-990.
Low S-K, Kuchiba A, Zembutsu H, et al. Genome-wide association study of pancreatic cancer in Japanese population. PLoS One. 2010;5:e11824.
Klein AP, Wolpin BM, Risch HA, et al. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun. 2018;9:556.
Campa D, Matarazzi M, Greenhalf W, et al. Genetic determinants of telomere length and risk of pancreatic cancer: a PANDoRA study. Int J Cancer. 2019;144:1275-1283.
Petersen GM, Amundadottir L, Fuchs CS, et al. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42:224-228.
Wu C, Miao X, Huang L, et al. Genome-wide association study identifies five loci associated with susceptibility to pancreatic cancer in Chinese populations. Nat Genet. 2011;44:62-66.
Wolpin BM, Rizzato C, Kraft P, et al. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer. Nat Genet. 2014;46:994-1000.
Campa D, Rizzato C, Stolzenberg-Solomon R, et al. TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. Int J Cancer. 2015;137:2175-2183.
Childs EJ, Mocci E, Campa D, et al. Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. Nat Genet. 2015;47:911-916.
Amundadottir LT. Pancreatic cancer genetics. Int J Biol Sci. 2016;12:314-325.
Campa D, Capurso G, Pastore M, et al. Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors. Sci Rep. 2016;6:39565.
Zhang M, Wang Z, Obazee O, et al. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. Oncotarget. 2016;7:66328-66343.
Piciucchi M, Capurso G, Valente R, et al. Early onset pancreatic cancer: risk factors, presentation and outcome. Pancreatology. 2015;15:151-155.
Raimondi S, Maisonneuve P, Lohr J-M, Lowenfels AB. Early onset pancreatic cancer: evidence of a major role for smoking and genetic factors. Cancer Epidemiol Biomarkers Prev. 2007;16:1894-1897.
McWilliams RR, Maisonneuve P, Bamlet WR, et al. Risk factors for early-onset and very-early-onset pancreatic adenocarcinoma: a pancreatic cancer case-control consortium (PanC4) analysis. Pancreas. 2016;45:311-316.
Ntala C, Debernardi S, Feakins RM, Crnogorac-Jurcevic T. Demographic, clinical, and pathological features of early onset pancreatic cancer patients. BMC Gastroenterol. 2018;18:139.
Ben-Aharon I, Elkabets M, Pelossof R, et al. Genomic landscape of pancreatic adenocarcinoma in younger versus older patients: does age matter? Clin Cancer Res. 2019;25:2185-2193.
Chen J, Wu X, Huang Y, et al. Identification of genetic variants predictive of early onset pancreatic cancer through a population science analysis of functional genomic datasets. Oncotarget. 2016;7:56480-56490.
Campa D, Rizzato C, Capurso G, et al. Genetic susceptibility to pancreatic cancer and its functional characterisation: the PANcreatic disease ReseArch (PANDoRA) consortium. Dig Liver Dis. 2013;45:95-99.
Boyle AP, Hong EL, Hariharan M, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22:1790-1797.
Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930-D934.
GTEx Project. GTEx portal. GTEx Anal. Release V6p (dbGaP Access. phs000424.v6.p1). 2017.
Dayem Ullah AZ, Oscanoa J, Wang J, Nagano A, Lemoine NR, Chelala C. SNPnexus: assessing the functional relevance of genetic variation to facilitate the promise of precision medicine. Nucleic Acids Res. 2018;46:W109-W113.
Hasegawa T, Asanuma H, Ogino J, et al. Use of potassium channel tetramerization domain-containing 12 as a biomarker for diagnosis and prognosis of gastrointestinal stromal tumor. Hum Pathol. 2013;44:1271-1277.
Zhong Y, Yang J, Xu WW, et al. KCTD12 promotes tumorigenesis by facilitating CDC25B/CDK1/Aurora A-dependent G2/M transition. Oncogene. 2017;36:6177-6189.
Khalid M, Idichi T, Seki N, et al. Gene regulation by antitumor miR-204-5p in pancreatic ductal adenocarcinoma: the clinical significance of direct RACGAP1 regulation. Cancers (Basel). 2019;11:327.
Kote-Jarai Z, Saunders EJ, Leongamornlert DA, et al. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. Hum Mol Genet. 2013;22:2520-2528.
Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians
Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women
Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk
