TY - JOUR
TI - Identification of Recessively Inherited Genetic Variants Potentially
Linked to Pancreatic Cancer Risk
AU - Lu, Ye
AU - Gentiluomo, Manuel
AU - Macauda, Angelica
AU - Gioffreda,
AU - Domenica
AU - Gazouli, Maria
AU - Petrone, Maria C.
AU - Kelemen, Dezso and
AU - Ginocchi, Laura
AU - Morelli, Luca
AU - Papiris, Konstantinos and
AU - Greenhalf, William
AU - Izbicki, Jakob R.
AU - Kiudelis, Vytautas and
AU - Mohelnikova-Duchonova, Beatrice
AU - Bueno-de-Mesquita, Bas
AU - Vodicka,
AU - Pavel
AU - Brenner, Hermann
AU - Diener, Markus K.
AU - Pezzilli, Raffaele
AU - and Ivanauskas, Audrius
AU - Salvia, Roberto
AU - Szentesi, Andrea and
AU - Aoki, Mateus Nobrega
AU - Nemeth, Balazs C.
AU - Sperti, Cosimo and
AU - Jamroziak, Krzysztof
AU - Chammas, Roger
AU - Oliverius, Martin and
AU - Archibugi, Livia
AU - Ermini, Stefano
AU - Novak, Janos
AU - Kupcinskas,
AU - Juozas
AU - Strouhal, Ondrej
AU - Soucek, Pavel
AU - Cavestro, Giulia M.
AU - and Milanetto, Anna C.
AU - Vanella, Giuseppe
AU - Neoptolemos, John P.
AU - and Theodoropoulos, George E.
AU - van Laarhoven, Hanneke W. M. and
AU - Mambrini, Andrea
AU - Moz, Stefania
AU - Kala, Zdenek
AU - Lovecek, Martin
AU - and Basso, Daniela
AU - Uzunoglu, Faik G.
AU - Hackert, Thilo
AU - Testoni,
AU - Sabrina G. G.
AU - Hlavac, Viktor
AU - Andriulli, Angelo
AU - Lucchesi,
AU - Maurizio
AU - Tavano, Francesca
AU - Carrara, Silvia
AU - Hegyi, Peter and
AU - Arcidiacono, Paolo G.
AU - Busch, Olivier R.
AU - Lawlor, Rita T. and
AU - Puzzono, Marta
AU - Boggi, Ugo
AU - Guo, Feng
AU - Malecka-Panas, Ewa and
AU - Capurso, Gabriele
AU - Landi, Stefano
AU - Talar-Wojnarowska, Renata and
AU - Strobel, Oliver
AU - Gao, Xin
AU - Vashist, Yogesh
AU - Campa, Daniele and
AU - Canzian, Federico
JO - Frontiers in Oncology
PY - 2021
VL - 11
TODO - null
SP - null
PB - Frontiers Media SA
SN - null
TODO - 10.3389/fonc.2021.771312
TODO - pancreatic cancer; susceptibility; genome-wide association study;
recessive model; genetic polymorphisms
TODO - Although 21 pancreatic cancer susceptibility loci have been identified
in individuals of European ancestry through genome-wide association
studies (GWASs), much of the heritability of pancreatic cancer risk
remains unidentified. A recessive genetic model could be a powerful tool
for identifying additional risk variants. To discover recessively
inherited pancreatic cancer risk loci, we performed a re-analysis of the
largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium
(PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4),
including 8,769 cases and 7,055 controls of European ancestry. Six
single nucleotide polymorphisms (SNPs) showed associations with
pancreatic cancer risk according to a recessive model of inheritance. We
replicated these variants in 3,212 cases and 3,470 controls collected
from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results
of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921
(8p23.2) and rs147904962 (17q21.31) showed specific recessive effects
(p<10(-5)) compared with the additive effects (p>10(-3)), although none
of the six SNPs reached the conventional threshold for genome-wide
significance (p < 5x10(-8)). Additional bioinformatic analysis explored
the functional annotations of the SNPs and indicated a possible
relationship between rs36018702 and expression of the BCL2L11 and BUB1
genes, which are known to be involved in pancreatic biology. Our
findings, while not conclusive, indicate the importance of considering
non-additive genetic models when performing GWAS analysis. The SNPs
associated with pancreatic cancer in this study could be used for
further meta-analysis for recessive association of SNPs and pancreatic
cancer risk and might be a useful addiction to improve the performance
of polygenic risk scores.
ER -