TY - JOUR
T1 - Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk
AU - Giaccherini, Matteo
AU - Farinella, Riccardo
AU - Gentiluomo, Manuel
AU - Mohelnikova-Duchonova, Beatrice
AU - Kauffmann, Emanuele Federico
AU - Palmeri, Matteo
AU - Uzunoglu, Faik
AU - Soucek, Pavel
AU - Petrauskas, Dalius
AU - Cavestro, Giulia Martina
AU - Zykus, Romanas
AU - Carrara, Silvia
AU - Pezzilli, Raffaele
AU - Puzzono, Marta
AU - Szentesi, Andrea
AU - Neoptolemos, John
AU - Archibugi, Livia
AU - Palmieri, Orazio
AU - Milanetto, Anna Caterina
AU - Capurso, Gabriele
AU - van Eijck, Casper H. J.
AU - Stocker, Hannah
AU - Lawlor, Rita T.
AU - Vodicka, Pavel
AU - Lovecek, Martin
AU - Izbicki, Jakob R.
AU - Perri, Francesco
AU - Kupcinskaite-Noreikiene, Rita
AU - Götz, Mara
AU - Kupcinskas, Juozas
AU - Hussein, Tamás
AU - Hegyi, P. ter
AU - Busch, Olivier R.
AU - Hackert, Thilo
AU - Mambrini, Andrea
AU - Brenner, Hermann
AU - Lucchesi, Maurizio
AU - Basso, Daniela
AU - Tavano, Francesca
AU - Schöttker, Ben
AU - Vanella, Giuseppe
AU - Bunduc, Stefania
AU - Petrányi, Ágota
AU - Landi, Stefano
AU - Morelli, Luca
AU - Canzian, Federico
AU - Campa, Daniele
N1 - Funding Information: This work was supported by Fondazione Tizzi (Pisa, Italy) and by Fondazione Arpa (Pisa, Italy, www.fondazionearpa.it ), by Ministry of Health, Czech Republic 19‐03‐00097 (Lovecek M.), NU21‐07‐00247 (Vodicka P); by Italian Ministry of Health grants to Fondazione “Casa Sollievo della Sofferenza” IRCCS Hospital, San Giovanni Rotondo (FG), Italy and by the “5x1000” voluntary contribution. Gabriele Capurso received support from AIRC (IG Grant 2021‐26201). Funding Information: We would like to thank the Center for Biological Resources at Humanitas Research Hospital and Dr Elena Finati, data manager. We would like to thank Prof. R.C.H. Vermeulen (University of Utrecht) and the late B. Bueno-de-Mesquita (National Institute for Public Health and the Environment) for the EPIC genotyping data used in the PANDoRA replication. Publisher Copyright: © 2022 UICC.
PY - 2023/7/15
Y1 - 2023/7/15
N2 - 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.
AB - 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.
KW - association study
KW - genetic susceptibility
KW - pancreatic ductal adenocarcinoma
KW - single nucleotide polymorphisms
UR - http://www.scopus.com/inward/record.url?scp=85144134666&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/ijc.34383
DO - https://doi.org/10.1002/ijc.34383
M3 - Article
C2 - 36451333
SN - 0020-7136
VL - 153
SP - 373
EP - 379
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 2
ER -