Smoking modifies pancreatic cancer risk loci on 2q21.3

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

doi:10.1158/0008-5472.CAN-20-3267

Smoking modifies pancreatic cancer risk loci on 2q21.3

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

Research output: Contribution to journal › Article › peer-review

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, P_interaction 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	https://doi.org/10.1158/0008-5472.CAN-20-3267
State	Published - Jun 1 2021

ASJC Scopus subject areas

Oncology
Cancer Research

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Mocci, E., Kundu, P., Wheeler, W., Arslan, A. A., Beane-Freeman, L. E., Bracci, P. M., Brennan, P., Canzian, F., Du, M., Gallinger, S., Giles, G. G., Goodman, P. J., Kooperberg, C., Le Marchand, L., Neale, R. E., Shu, X. O., Visvanathan, K., White, E., Zheng, W., ... Stolzenberg-Solomon, R. (2021). Smoking modifies pancreatic cancer risk loci on 2q21.3. Cancer Research, 81(11), 3134-3143. https://doi.org/10.1158/0008-5472.CAN-20-3267

Mocci, E, Kundu, P, Wheeler, W, Arslan, AA, Beane-Freeman, LE, Bracci, PM, Brennan, P, Canzian, F, Du, M, Gallinger, S, Giles, GG, Goodman, PJ, Kooperberg, C, Le Marchand, L, Neale, RE, Shu, XO, Visvanathan, K, White, E, Zheng, W, Albanes, D, Andreotti, G, Babic, A, Bamlet, WR, Berndt, SI, Blackford, AL, Bueno-De-Mesquita, B, Buring, JE, Campa, D, Chanock, SJ, Childs, EJ, Duell, EJ, Fuchs, CS, Gaziano, JM, Giovannucci, EL, Goggins, MG, Hartge, P, Hassan, MM, Holly, EA, Hoover, RN, Hung, RJ, Kurtz, RC, Lee, IM, Malats, N, Milne, RL, Ng, K, Oberg, AL, Panico, S, Peters, U, Porta, M, Rabe, KG, Riboli, E, Rothman, N, Scelo, G, Sesso, HD, Silverman, DT, Stevens, VL, Strobel, O, Thompson, IM, Tjonneland, A, Trichopoulou, A, van Den Eeden, SK, Wactawski-Wende, J, Wentzensen, N, Wilkens, LR, Yu, H, Yuan, F, Zeleniuch-Jacquotte, A, Amundadottir, LT, Li, D, Jacobs, EJ, Petersen, GM, Wolpin, BM, Risch, HA, Kraft, P, Chatterjee, N , Klein, AP & Stolzenberg-Solomon, R 2021, 'Smoking modifies pancreatic cancer risk loci on 2q21.3', Cancer Research, vol. 81, no. 11, pp. 3134-3143. https://doi.org/10.1158/0008-5472.CAN-20-3267

@article{852a3f623d444e3c8b1cd5cc0281e577,

title = "Smoking modifies pancreatic cancer risk loci on 2q21.3",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",

year = "2021",

month = jun,

day = "1",

doi = "10.1158/0008-5472.CAN-20-3267",

language = "English (US)",

volume = "81",

pages = "3134--3143",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "11",

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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

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.

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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

SN - 0008-5472

VL - 81

SP - 3134

EP - 3143

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -

Smoking modifies pancreatic cancer risk loci on 2q21.3

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