Abstract
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 < 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 ¼ 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 ¼ 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3134-3143 |
| Number of pages | 10 |
| Journal | Cancer Research |
| Volume | 81 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jun 1 2021 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Smoking modifies pancreatic cancer risk loci on 2q21.3. / Mocci, Evelina; Kundu, Prosenjit; Wheeler, William et al.
In: Cancer Research, Vol. 81, No. 11, 01.06.2021, p. 3134-3143.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Smoking modifies pancreatic cancer risk loci on 2q21.3
AU - Mocci, Evelina
AU - Kundu, Prosenjit
AU - Wheeler, William
AU - Arslan, Alan A.
AU - Beane-Freeman, Laura E.
AU - Bracci, Paige M.
AU - Brennan, Paul
AU - Canzian, Federico
AU - Du, Mengmeng
AU - Gallinger, Steven
AU - Giles, Graham G.
AU - Goodman, Phyllis J.
AU - Kooperberg, Charles
AU - Le Marchand, Loic
AU - Neale, Rachel E.
AU - Shu, Xiao Ou
AU - Visvanathan, Kala
AU - White, Emily
AU - Zheng, Wei
AU - Albanes, Demetrius
AU - Andreotti, Gabriella
AU - Babic, Ana
AU - Bamlet, William R.
AU - Berndt, Sonja I.
AU - Blackford, Amanda L.
AU - Bueno-De-Mesquita, Bas
AU - Buring, Julie E.
AU - Campa, Daniele
AU - Chanock, Stephen J.
AU - Childs, Erica J.
AU - Duell, Eric J.
AU - Fuchs, Charles S.
AU - Gaziano, J. Michael
AU - Giovannucci, Edward L.
AU - Goggins, Michael G.
AU - Hartge, Patricia
AU - Hassan, Manal M.
AU - Holly, Elizabeth A.
AU - Hoover, Robert N.
AU - Hung, Rayjean J.
AU - Kurtz, Robert C.
AU - Lee, I. Min
AU - Malats, Nuria
AU - Milne, Roger L.
AU - Ng, Kimmie
AU - Oberg, Ann L.
AU - Panico, Salvatore
AU - Peters, Ulrike
AU - Porta, Miquel
AU - Rabe, Kari G.
AU - Riboli, Elio
AU - Rothman, Nathaniel
AU - Scelo, Ghislaine
AU - Sesso, Howard D.
AU - Silverman, Debra T.
AU - Stevens, Victoria L.
AU - Strobel, Oliver
AU - Thompson, Ian M.
AU - Tjonneland, Anne
AU - Trichopoulou, Antonia
AU - van Den Eeden, Stephen K.
AU - Wactawski-Wende, Jean
AU - Wentzensen, Nicolas
AU - Wilkens, Lynne R.
AU - Yu, Herbert
AU - Yuan, Fangcheng
AU - Zeleniuch-Jacquotte, Anne
AU - Amundadottir, Laufey T.
AU - Li, Donghui
AU - Jacobs, Eric J.
AU - Petersen, Gloria M.
AU - Wolpin, Brian M.
AU - Risch, Harvey A.
AU - Kraft, Peter
AU - Chatterjee, Nilanjan
AU - Klein, Alison P.
AU - Stolzenberg-Solomon, Rachael
N1 - Funding Information: The Women's Health Study was supported by research grants CA182913, CA-047988, HL-043851, HL-080467, and HL-099355 from the National Institutes of Health, Bethesda, MD. Funding Information: This work was supported by RO1CA154823 and P50CA062924 (to principal investigator A.P. Klein), R01 HG010480-01 (to principal investigator N. Chatterjee), Patient-Centered Outcomes Research Institute Award (ME-1602-34530), and the Intramural Research Program, Division of Cancer Epidemiology and Genetics, NCI (to principal investigator R. Stolzenberg-Solomon). Funding for the parent studies are listed below. Funding Information: The Shanghai Men's Health Study is supported by NIH grant UM1CA173640. The Shanghai Women's Health Study is supported by NIH grant UM1CA182910. Funding Information: SELECT study is supported by NIH grant award number U10 CA37429 (C.D. Blanke), and UM1 CA182883 (C.M. Tangen/I.M. Thompson). The authors thank the site investigators and staff and, most importantly, the participants from PCPT and SELECT who donated their time to this trial. Funding Information: The work at Johns Hopkins University (Baltimore, MD) was supported by the NCI grants P50CA062924 and R01CA97075. Additional support was provided by the Lustgarten Foundation, Susan Wojcicki and Dennis Troper, and the Sol Goldman Pancreas Cancer Research Center. This work was supported by RO1 CA154823 and federal funds from the NCI, U.S. NIH under contract number HHSN261200800001E. Funding Information: The IARC/Central Europe study was supported by a grant from the U.S. NCI at the NIH (R03 CA123546-02) and grants from the Ministry of Health of the Czech Republic (NR 9029-4/2006, NR9422-3, NR9998-3, MH CZ-DRO-MMCI 00209805). Funding Information: Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414, and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Funding Information: Health Professionals Follow-up Study is supported by NIH grant UM1 CA167552. from the NCI, Bethesda, MD. Funding Information: The GTEx Project was supported by the Common Fund of the Office of the Director of the NIH, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this article were obtained from: (https://gtexportal. org/home/) the GTEx Project Portal on June 30, 2019 and July 30, 2020 and/or dbGaP accession number phs000424.vN.pN on June 30, 2019. Funding Information: The Mayo Clinic Biospecimen Resource for Pancreas Research study is supported by the Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). Funding Information: The WHI program is funded by the National Heart, Lung, and Blood Institute, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at: http:// www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI% 20Investigator%20Long%20List.pdf. Funding Information: The PACIFIC Study was supported by RO1CA102765, Kaiser Permanente and Group Health Cooperative. Funding Information: The NYU study (A. Zeleniuch-Jacquotte and A.A. Arslan) was funded by NIH R01 CA098661, UM1 CA182934 and center grants P30 CA016087 and P30 ES000260. Funding Information: Additional support from the Hale Center for Pancreatic Cancer Research, U01 CA21017 from the NCI, Bethesda, MD, and the United States Department of Defense CA130288, Lustgarten Foundation, Pancreatic Cancer Action Network, Noble Effort Fund, Peter R. Leavitt Family Fund, Wexler Family Fund, and Promises for Purple to B.M. Wolpin. Funding Information: The authors acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data. They thank all the CLUE participants. Funding Information: Nurses' Health Study is supported by NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449 from the NCI, Bethesda, MD. Funding Information: The UCSF pancreas study was supported by NIH-NCI grants (R01CA1009767, R01CA109767-S1, and R0CA059706) and the Joan Rombauer Pancreatic Cancer Fund. Collection of cancer incidence data was supported by the California Department of Public Health as part of the statewide cancer reporting program; the NCI's SEER Program under contract HSN261201000140C awarded to CPIC; and the CDC's National Program of Cancer Registries, under agreement #U58DP003862-01 awarded to the California Department of Public Health. Funding Information: The Yale (CT) pancreas cancer study is supported by NCI at the U.S. NIH, grant 5R01CA098870. The cooperation of 30 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. The Connecticut Pancreas Cancer Study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in that study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data. Funding Information: The PANKRAS II Study in Spain was supported by research grants from Instituto de Salud Carlos III-FEDER, Spain: Fondo de Investigaciones Sanitarias (FIS; #PI13/ 00082 and #PI15/01573) and Red Temática de Investigación Cooperativa en Cáncer, Spain (#RD12/0036/0050); and European Cooperation in Science and Technology (COST Action #BM1204: EU_Pancreas), Ministerio de Ciencia y Tecnología (CICYT SAF 2000-0097), Fondo de Investigación Sanitaria (95/0017), Madrid, Spain; Gen-eralitat de Catalunya (CIRIT - SGR); “Red temática de investigación cooperativa de centros en Cáncer” (C03/10), “Red temática de investigación cooperativa de centros en Epidemiología y salud pública” (C03/09), and CIBER de Epidemiología (CIBER-ESP), Madrid. Funding Information: Studies included in PANDoRA were partly funded by: the Czech Science Foundation (no. P301/12/1734), the Internal Grant Agency of the Czech Ministry of Health (IGA NT 13 263); the Baden-Wu€rttemberg State Ministry of Research, Science and Arts (H. Brenner), the Heidelberger EPZ-Pancobank (M.W. Bu€chler and team: T. Hackert, N.A. Giese, Ch. Tjaden, E. Soyka, M. Meinhardt; Heidelberger Stiftung Chirurgie and BMBF grant 01GS08114), the BMBH (P. Schirmacher; BMBF grant 01EY1101), the “5x1000” voluntary contribution of the Italian Government, the Italian Ministry of Health (RC1203GA57, RC1303GA53, RC1303GA54, RC1303GA50), the Italian Association for Research on Cancer (A. Scarpa; AIRC n. 12182), the Italian Ministry of Research (A. Scarpa; FIRB - RBAP10AHJB), the Italian FIMP-Ministry of Health (A. Scarpa; 12 CUP_J33G13000210001), and by the National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, UK. The authors would like to acknowledge the contribution of Frederike Dijk and Oliver Busch (Academic Medical Center, Amsterdam, the Netherlands). Funding Information: The Queensland Pancreatic Cancer Study was supported by a grant from the National Health and Medical Research Council of Australia (NHMRC; grant number 442302). R.E. Neale is supported by a NHMRC Senior Research Fellowship (#1060183). Funding Information: The Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry is supported by P30CA008748, the Geoffrey Beene Foundation, the Arnold and Arlene Goldstein Family Foundation, and the Society of MSKCC. We acknowledge the contribution of Irene Orlow, MS, PhD to this analysis. Publisher Copyright: © 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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 < 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 ¼ 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 ¼ 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.
AB - 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 < 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 ¼ 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 ¼ 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.
UR - http://www.scopus.com/inward/record.url?scp=85106990137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85106990137&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-20-3267
DO - 10.1158/0008-5472.CAN-20-3267
M3 - Article
C2 - 33574088
AN - SCOPUS:85106990137
VL - 81
SP - 3134
EP - 3143
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -