Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk

Matteo Giaccherini¹, Riccardo Farinella¹, Manuel Gentiluomo¹, Beatrice Mohelnikova-Duchonova², Emanuele Federico Kauffmann³, Matteo Palmeri⁴, Faik Uzunoglu⁵, Pavel Soucek⁶, Dalius Petrauskas⁷, Giulia Martina Cavestro⁸, Romanas Zykus⁷, Silvia Carrara⁹, Raffaele Pezzilli¹⁰, Marta Puzzono⁸, Andrea Szentesi^{11

12

13}, John Neoptolemos¹⁴, Livia Archibugi^{15

16}, Orazio Palmieri¹⁷, Anna Caterina Milanetto¹⁸, Gabriele Capurso^{15

16}, Casper H J van Eijck¹⁹, Hannah Stocker²⁰, Rita T Lawlor²¹, Pavel Vodicka^{22

23

24}, Martin Lovecek²⁵, Jakob R Izbicki⁵, Francesco Perri¹⁷, Rita Kupcinskaite-Noreikiene⁷, Mara Götz⁵, Juozas Kupcinskas⁷, Tamás Hussein^{26

27}, Péter Hegyi^{11

12

26

27}, Olivier R Busch²⁸, Thilo Hackert¹⁴, Andrea Mambrini²⁹, Hermann Brenner²⁰, Maurizio Lucchesi²⁹, Daniela Basso³⁰, Francesca Tavano¹⁷, Ben Schöttker²⁰, Giuseppe Vanella^{15

16}, Stefania Bunduc^{26

27

31}, Ágota Petrányi^{27

32}, Stefano Landi¹, Luca Morelli³³, Federico Canzian³⁴, Daniele Campa¹

Affiliations

¹ Department of Biology, University of Pisa, Pisa, Italy.
² Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
³ Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy.
⁴ General Surgery Unit, Department of Translational Research and new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
⁵ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Toxicogenomics Unit, Centre of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic.
⁷ Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁸ Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁹ Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.
¹⁰ Potenza Medical County Association, Potenza, Italy.
¹¹ Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
¹² János Szentágothai Research Center, University of Pécs, Pécs, Hungary.
¹³ Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary.
¹⁴ Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
¹⁵ Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
¹⁶ Digestive and Liver Disease Unit, Sant' Andrea Hospital, Rome, Italy.
¹⁷ Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, Foggia, Italy.
¹⁸ Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
¹⁹ Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
²⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
²² Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
²³ Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
²⁴ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
²⁵ Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic.
²⁶ Center for Translational Medicine, Semmelweis University, Budapest, Hungary.
²⁷ Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
²⁸ Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
²⁹ Oncological Department Massa Carrara, Azienda USL Toscana Nord Ovest, Carrara, Italy.
³⁰ Department of Medicine, University of Padova, Padova, Italy.
³¹ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
³² Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary.
³³ General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
³⁴ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 36451333
DOI: 10.1002/ijc.34383

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk

Matteo Giaccherini et al. Int J Cancer. 2023.

. 2023 Jul 15;153(2):373-379.

doi: 10.1002/ijc.34383. Epub 2022 Dec 14.

Authors

Affiliations

¹ Department of Biology, University of Pisa, Pisa, Italy.
² Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Olomouc, Czech Republic.
³ Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy.
⁴ General Surgery Unit, Department of Translational Research and new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
⁵ Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Toxicogenomics Unit, Centre of Toxicology and Health Safety, National Institute of Public Health, Prague, Czech Republic.
⁷ Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
⁸ Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy.
⁹ Endoscopic Unit, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.
¹⁰ Potenza Medical County Association, Potenza, Italy.
¹¹ Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary.
¹² János Szentágothai Research Center, University of Pécs, Pécs, Hungary.
¹³ Centre for Translational Medicine, Department of Medicine, University of Szeged, Szeged, Hungary.
¹⁴ Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
¹⁵ Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.
¹⁶ Digestive and Liver Disease Unit, Sant' Andrea Hospital, Rome, Italy.
¹⁷ Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, Foggia, Italy.
¹⁸ Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy.
¹⁹ Department of Surgery, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
²⁰ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²¹ ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy.
²² Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
²³ Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
²⁴ Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic.
²⁵ Department of Surgery I, University Hospital Olomouc, Olomouc, Czech Republic.
²⁶ Center for Translational Medicine, Semmelweis University, Budapest, Hungary.
²⁷ Division of Pancreatic Diseases, Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
²⁸ Department of Surgery, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
²⁹ Oncological Department Massa Carrara, Azienda USL Toscana Nord Ovest, Carrara, Italy.
³⁰ Department of Medicine, University of Padova, Padova, Italy.
³¹ Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
³² Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary.
³³ General Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
³⁴ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 36451333
DOI: 10.1002/ijc.34383

Abstract

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10^-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

Keywords: association study; genetic susceptibility; pancreatic ductal adenocarcinoma; single nucleotide polymorphisms.

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References

REFERENCES

1. Ferlay J, Colombet M, Soerjomataram I, et al. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021;149(4):778-789.
1. Lu Y, Gentiluomo M, Lorenzo-Bermejo J, et al. Mendelian randomisation study of the effects of known and putative risk factors on pancreatic cancer. J Med Genet. 2020;57(12):820-828.
1. Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18(7):493-502.
1. Gentiluomo M, Canzian F, Nicolini A, Gemignani F, Landi S, Campa D. Germline genetic variability in pancreatic cancer risk and prognosis. Semin Cancer Biol. 2022;79:105-131.
1. Galeotti AA, Gentiluomo M, Rizzato C, et al. Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction. J Med Genet. 2020;58:369-377.

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Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk

Affiliations

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk

Authors

Affiliations

Abstract

References

REFERENCES

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous