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

Daniele Campa; Manuela Pastore; Manuel Gentiluomo; Renata Talar-Wojnarowska; Juozas Kupcinskas; Ewa Malecka-Panas; John P. Neoptolemos; Willem Niesen; Pavel Vodicka; Gianfranco Delle Fave; H. Bas Bueno-de-Mesquita; Maria Gazouli; Paola Pacetti; Milena Di Leo; Hidemi Ito; Harald Klüter; Pavel Soucek; Vincenzo Corbo; Kenji Yamao; Satoyo Hosono; Rudolf Kaaks; Yogesh Vashist; Domenica Gioffreda; Oliver Strobel; Yasuhiro Shimizu; Frederike Dijk; Angelo Andriulli; Audrius Ivanauskas; Peter Bugert; Francesca Tavano; Ludmila Vodickova; Carlo Federico Zambon; Martin Lovecek; Stefano Landi; Timothy J. Key; Ugo Boggi; Raffaele Pezzilli; Krzysztof Jamroziak; Beatrice Mohelnikova-Duchonova; Andrea Mambrini; Franco Bambi; Olivier Busch; Valerio Pazienza; Roberto Valente; George E. Theodoropoulos; Thilo Hackert; Gabriele Capurso; Giulia Martina Cavestro; Claudio Pasquali; Daniela Basso; Cosimo Sperti; Keitaro Matsuo; Markus Büchler; Kay-Tee Khaw; Jakob Izbicki; Eithne Costello; Verena Katzke; Christoph Michalski; Anna Stepien; Cosmeri Rizzato; Federico Canzian

doi:https://doi.org/10.18632/oncotarget.10935

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

Daniele Campa, Manuela Pastore, Manuel Gentiluomo, Renata Talar-Wojnarowska, Juozas Kupcinskas, Ewa Malecka-Panas, John P. Neoptolemos, Willem Niesen, Pavel Vodicka, Gianfranco Delle Fave, H. Bas Bueno-de-Mesquita, Maria Gazouli, Paola Pacetti, Milena Di Leo, Hidemi Ito, Harald Klüter, Pavel Soucek, Vincenzo Corbo, Kenji Yamao, Satoyo HosonoRudolf Kaaks, Yogesh Vashist, Domenica Gioffreda, Oliver Strobel, Yasuhiro Shimizu, Frederike Dijk, Angelo Andriulli, Audrius Ivanauskas, Peter Bugert, Francesca Tavano, Ludmila Vodickova, Carlo Federico Zambon, Martin Lovecek, Stefano Landi, Timothy J. Key, Ugo Boggi, Raffaele Pezzilli, Krzysztof Jamroziak, Beatrice Mohelnikova-Duchonova, Andrea Mambrini, Franco Bambi, Olivier Busch, Valerio Pazienza, Roberto Valente, George E. Theodoropoulos, Thilo Hackert, Gabriele Capurso, Giulia Martina Cavestro, Claudio Pasquali, Daniela Basso, Cosimo Sperti, Keitaro Matsuo, Markus Büchler, Kay-Tee Khaw, Jakob Izbicki, Eithne Costello, Verena Katzke, Christoph Michalski, Anna Stepien, Cosmeri Rizzato, Federico Canzian

Research output: Contribution to journal › Article › Academic › peer-review

39 Citations (Scopus)

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

Original language	English
Pages (from-to)	57011-57020
Journal	Oncotarget
Volume	7
Issue number	35
DOIs	https://doi.org/10.18632/oncotarget.10935
Publication status	Published - 2016

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https://doi.org/10.18632/oncotarget.10935

Cite this

Campa, D., Pastore, M., Gentiluomo, M., Talar-Wojnarowska, R., Kupcinskas, J., Malecka-Panas, E., Neoptolemos, J. P., Niesen, W., Vodicka, P., Delle Fave, G., Bueno-de-Mesquita, H. B., Gazouli, M., Pacetti, P., Di Leo, M., Ito, H., Klüter, H., Soucek, P., Corbo, V., Yamao, K., ... Canzian, F. (2016). Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk. Oncotarget, 7(35), 57011-57020. https://doi.org/10.18632/oncotarget.10935

@article{bc5f328bfdd04242b9034ac4ce958930,

title = "Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk",

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",

author = "Daniele Campa and Manuela Pastore and Manuel Gentiluomo and Renata Talar-Wojnarowska and Juozas Kupcinskas and Ewa Malecka-Panas and Neoptolemos, {John P.} and Willem Niesen and Pavel Vodicka and {Delle Fave}, Gianfranco and Bueno-de-Mesquita, {H. Bas} and Maria Gazouli and Paola Pacetti and {Di Leo}, Milena and Hidemi Ito and Harald Kl{\"u}ter and Pavel Soucek and Vincenzo Corbo and Kenji Yamao and Satoyo Hosono and Rudolf Kaaks and Yogesh Vashist and Domenica Gioffreda and Oliver Strobel and Yasuhiro Shimizu and Frederike Dijk and Angelo Andriulli and Audrius Ivanauskas and Peter Bugert and Francesca Tavano and Ludmila Vodickova and Zambon, {Carlo Federico} and Martin Lovecek and Stefano Landi and Key, {Timothy J.} and Ugo Boggi and Raffaele Pezzilli and Krzysztof Jamroziak and Beatrice Mohelnikova-Duchonova and Andrea Mambrini and Franco Bambi and Olivier Busch and Valerio Pazienza and Roberto Valente and Theodoropoulos, {George E.} and Thilo Hackert and Gabriele Capurso and Cavestro, {Giulia Martina} and Claudio Pasquali and Daniela Basso and Cosimo Sperti and Keitaro Matsuo and Markus B{\"u}chler and Kay-Tee Khaw and Jakob Izbicki and Eithne Costello and Verena Katzke and Christoph Michalski and Anna Stepien and Cosmeri Rizzato and Federico Canzian",

year = "2016",

doi = "https://doi.org/10.18632/oncotarget.10935",

language = "English",

volume = "7",

pages = "57011--57020",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "35",

}

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, K-T, Izbicki, J, Costello, E, Katzke, V, Michalski, C, Stepien, A, Rizzato, C & Canzian, F 2016, 'Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk', Oncotarget, vol. 7, no. 35, pp. 57011-57020. https://doi.org/10.18632/oncotarget.10935

TY - JOUR

T1 - Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

AU - Campa, Daniele

AU - Pastore, Manuela

AU - Gentiluomo, Manuel

AU - Talar-Wojnarowska, Renata

AU - Kupcinskas, Juozas

AU - Malecka-Panas, Ewa

AU - Neoptolemos, John P.

AU - Niesen, Willem

AU - Vodicka, Pavel

AU - Delle Fave, Gianfranco

AU - Bueno-de-Mesquita, H. Bas

AU - Gazouli, Maria

AU - Pacetti, Paola

AU - Di Leo, Milena

AU - Ito, Hidemi

AU - Klüter, Harald

AU - Soucek, Pavel

AU - Corbo, Vincenzo

AU - Yamao, Kenji

AU - Hosono, Satoyo

AU - Kaaks, Rudolf

AU - Vashist, Yogesh

AU - Gioffreda, Domenica

AU - Strobel, Oliver

AU - Shimizu, Yasuhiro

AU - Dijk, Frederike

AU - Andriulli, Angelo

AU - Ivanauskas, Audrius

AU - Bugert, Peter

AU - Tavano, Francesca

AU - Vodickova, Ludmila

AU - Zambon, Carlo Federico

AU - Lovecek, Martin

AU - Landi, Stefano

AU - Key, Timothy J.

AU - Boggi, Ugo

AU - Pezzilli, Raffaele

AU - Jamroziak, Krzysztof

AU - Mohelnikova-Duchonova, Beatrice

AU - Mambrini, Andrea

AU - Bambi, Franco

AU - Busch, Olivier

AU - Pazienza, Valerio

AU - Valente, Roberto

AU - Theodoropoulos, George E.

AU - Hackert, Thilo

AU - Capurso, Gabriele

AU - Cavestro, Giulia Martina

AU - Pasquali, Claudio

AU - Basso, Daniela

AU - Sperti, Cosimo

AU - Matsuo, Keitaro

AU - Büchler, Markus

AU - Khaw, Kay-Tee

AU - Izbicki, Jakob

AU - Costello, Eithne

AU - Katzke, Verena

AU - Michalski, Christoph

AU - Stepien, Anna

AU - Rizzato, Cosmeri

AU - Canzian, Federico

PY - 2016

Y1 - 2016

N2 - 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

AB - 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

U2 - https://doi.org/10.18632/oncotarget.10935

DO - https://doi.org/10.18632/oncotarget.10935

M3 - Article

C2 - 27486979

SN - 1949-2553

VL - 7

SP - 57011

EP - 57020

JO - Oncotarget

JF - Oncotarget

IS - 35

ER -