Smoking Modifies Pancreatic Cancer Risk Loci on 2q21.3
Authors: Mocci Evelina , Kundu Prosenjit , Wheeler William , Arslan Alan A. , Beane-Freeman Laura E. , Bracci Paige M. , Brennan Paul , Canzian Federico , Du Mengmeng , Gallinger Steven , Giles Graham G. , Goodman Phyllis J. , Kooperberg Charles , Le Marchand Loic , Neale Rachel E. , Shu Xiao-Ou , Visvanathan Kala , White Emily , Zheng Wei , Albanes Demetrius , Andreotti Gabriella , Babic Ana , Bamlet William R. , Berndt Sonja I. , Blackford Amanda L. , Bueno-de-Mesquita Bas , Buring Julie E. , Campa Daniele , Chanock Stephen J. , Childs Erica J. , Duell Eric J. , Fuchs Charles S. , Gaziano J. Michael , Giovannucci Edward L. , Goggins Michael G. , Hartge Patricia , Hassan Manal M. , Holly Elizabeth A. , Hoover Robert N. , Hung Rayjean J. , Kurtz Robert C. , Lee I-Min , Malats Núria , Milne Roger L. , Ng Kimmie , Oberg Ann L. , Panico Salvatore , Peters Ulrike , Porta Miquel , Rabe Kari G. , Riboli Elio , Rothman Nathaniel , Scelo Ghislaine , Sesso Howard D. , Silverman Debra T. , Stevens Victoria L. , Strobel Oliver , Thompson Ian M. , Tjonneland Anne , Trichopoulou Antonia , Van Den Eeden Stephen K. , Wactawski-Wende Jean , Wentzensen Nicolas , Wilkens Lynne R. , Yu Herbert , Yuan Fangcheng , Zeleniuch-Jacquotte Anne , Amundadottir Laufey T. , Li Donghui , Jacobs Eric J. , Petersen Gloria M. , Wolpin Brian M. , Risch Harvey A. , Kraft Peter , Chatterjee Nilanjan , Klein Alison P. , Stolzenberg-Solomon Rachael 
Published: February 2021

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P &lt; 5 × 10–8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82–0.93; former smokers 1.00, 95% CI, 0.91–1.07; current smokers 1.25, 95% CI 1.12–1.40, Pinteraction = 3.08 × 10–9). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (r2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings.

Significance:

This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.