Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma
Chiara Corradi, Giulia Lencioni, Manuel Gentiluomo, Alessio Felici, Anna Latiano, Gediminas Kiudelis, Casper H.J. van Eijck, Katalin Marta, Rita T. Lawlor, Francesca Tavano, Ugo Boggi, Frederike Dijk, Giulia Martina Cavestro, Roel Vermeulen, Thilo Hackert, Maria Chiara Petrone, Faik G. Uzunoǧlu, Lívia Archibugi, Jakob R. Izbicki, Luca Morelli, Alessandro Zerbi, Stefano Landi, Hannah Stocker, Renata Talar‐Wojnarowska, Gregorio Di Franco, Péter Hegyi, Cosimo Sperti, Silvia Carrara, Gabriele Capurso, Maria Gazouli, Hermann Brenner, Ștefania Bunduc, Olivier R. Busch, Francesco Perri, Martin Oliverius, Péter Jenő Hegyi, Mara Göetz, Pasquale Scognamiglio, Andrea Mambrini, Paolo Giorgio Arcidiacono, Edita Kreivėnaitė, Juozas Kupčinskas, Tamás Hussein, Stefano Ermini, Anna Caterina Milanetto, Pavel Vodička, Vytautas Kiudelis, Viktor Hlaváč, Pavel Souček, George Theodoropoulos, Daniela Basso, John P. Neoptolemos, Mateus Nóbrega Aoki, Raffaele Pezzilli, Claudio Pasquali, Roger Chammas, Sabrina Gloria Giulia Testoni, Beatrice Mohelníková-Duchoňová, M Lucchesi, Cosmeri Rizzato, Federico Canzian, Daniele Campa
Abstract
Introduction Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. Materials and methods We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case–Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. Results The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10 −8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense ( RCCD1-AS1 ) gene which, when expressed, decreases the expression of the RCC1 domain-containing ( RCCD1 ) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1 . Conclusion We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.