Rayjean J Hung1, Margaret R Spitz2, Richard S Houlston3, Ann G Schwartz4, John K Field5, Jun Ying6, Yafang Li2, Younghun Han2, Xuemei Ji7, Wei Chen8, Xifeng Wu8, Ivan P Gorlov7, Jie Na9, Mariza de Andrade9, Geoffrey Liu10, Yonathan Brhane1, Nancy Diao11, Angela Wenzlaff4, Michael P A Davies5, Triantafillos Liloglou5, Maria Timofeeva12, Thomas Muley13, Hedy Rennert14, Walid Saliba14, Bríd M Ryan15, Elise Bowman15, Juan-Miguel Barros-Dios16, Mónica Pérez-Ríos16, Hal Morgenstern17, Shanbeh Zienolddiny18, Vidar Skaug18, Donatella Ugolini19, Stefano Bonassi20, Erik H F M van der Heijden21, Adonina Tardon22, Stig E Bojesen23, Maria Teresa Landi24, Mattias Johansson25, Heike Bickeböller26, Susanne Arnold27, Loic Le Marchand28, Olle Melander29, Angeline Andrew30, Kjell Grankvist31, Neil Caporaso24, M Dawn Teare32, Matthew B Schabath33, Melinda C Aldrich34, Lambertus A Kiemeney21, H-Erich Wichmann35, Philip Lazarus36, Jose Mayordomo37, Monica Neri38, Aage Haugen18, Zuo-Feng Zhang39, Alberto Ruano-Raviña16, Hermann Brenner40, Curtis C Harris15, Irene Orlow41, Gadi Rennert14, Angela Risch42, Paul Brennan25, David C Christiani11, Christopher I Amos2, Ping Yang43, Olga Y Gorlova44. 1. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. 2. Baylor College of Medicine, Houston, Texas. 3. Institute of Cancer Research, London, United Kingdom. 4. Wayne State University, Detroit, Michigan. 5. University of Liverpool, Liverpool, United Kingdom. 6. University of Texas McGovern Medical School, Houston, Texas. 7. Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. 8. The University of Texas, MD Anderson Cancer Center, Houston, Texas. 9. Mayo Clinic, Rochester, Minnesota. 10. Princess Margaret Cancer Center, Toronto, Ontario, Canada. 11. Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 12. German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Edinburgh, Edinburgh, United Kingdom. 13. German Center for Lung Research, Heidelberg, Germany; University Hospital Heidelberg, Heidelberg, Germany. 14. Technion-Israel Institute of Technology, Haifa, Israel. 15. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. 16. University of Santiago de Compostela, Praza do Obradoiro, Coruña, Spain. 17. Medical School, University of Michigan, Ann Arbor, Michigan. 18. National Institute of Occupational Health (STAMI), Oslo, Norway. 19. University of Genoa, Genoa, Italy. 20. San Raffaele University, Rome, Italy; San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy. 21. Radboud University Medical Center, Nijmegen, Netherlands. 22. University of Oviedo and CIBERESP, Oviedo, Spain. 23. Copenhagen University Hospital, Copenhagen, Denmark. 24. National Cancer Institute, Bethesda, Maryland. 25. International Agency for Research on Cancer, Lyon, France. 26. University Medical Center Goettingen, Goettingen, Germany. 27. University of Kentucky, Lexington, Kentucky. 28. University of Hawaii Cancer Center, Honolulu, Hawaii. 29. Lund University, Lund, Sweden. 30. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. 31. Umeå University, Umeå, Sweden. 32. University of Sheffield, Sheffield, United Kingdom. 33. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. 34. Vanderbilt University Medical Center, Nashville, Tennessee. 35. Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Bavaria, Germany. 36. Washington State University, Spokane, Washington. 37. University of Colorado, Aurora, Colorado. 38. San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy. 39. University of California - Los Angeles, Los Angeles, California. 40. German Cancer Research Center (DKFZ), Heidelberg, Germany. 41. Memorial Sloan Kettering Cancer Center, New York, New York. 42. German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Salzburg, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria. 43. Mayo Clinic, Scottsdale, Arizona. 44. Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Electronic address: olga.y.gorlova@dartmouth.edu.
Abstract
INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.
INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.
Authors: Linda Kachuri; Christopher I Amos; James D McKay; Mattias Johansson; Paolo Vineis; H Bas Bueno-de-Mesquita; Marie-Christine Boutron-Ruault; Mikael Johansson; J Ramón Quirós; Sabina Sieri; Ruth C Travis; Elisabete Weiderpass; Loic Le Marchand; Brian E Henderson; Lynne Wilkens; Gary E Goodman; Chu Chen; Jennifer A Doherty; David C Christiani; Yongyue Wei; Li Su; Shelley Tworoger; Xuehong Zhang; Peter Kraft; David Zaridze; John K Field; Michael W Marcus; Michael P A Davies; Russell Hyde; Neil E Caporaso; Maria Teresa Landi; Gianluca Severi; Graham G Giles; Geoffrey Liu; John R McLaughlin; Yafang Li; Xiangjun Xiao; Gord Fehringer; Xuchen Zong; Robert E Denroche; Philip C Zuzarte; John D McPherson; Paul Brennan; Rayjean J Hung Journal: Carcinogenesis Date: 2015-11-20 Impact factor: 4.944
Authors: Gordon Fehringer; Darren R Brenner; Zuo-Feng Zhang; Yuan-Chin Amy Lee; Keitaro Matsuo; Hidemi Ito; Qing Lan; Paolo Vineis; Mattias Johansson; Kim Overvad; Elio Riboli; Antonia Trichopoulou; Carlotta Sacerdote; Isabelle Stucker; Paolo Boffetta; Paul Brennan; David C Christiani; Yun-Chul Hong; Maria Teresa Landi; Hal Morgenstern; Ann G Schwartz; Angela S Wenzlaff; Gad Rennert; John R McLaughlin; Curtis C Harris; Susan Olivo-Marston; Irene Orlow; Bernard J Park; Marjorie Zauderer; Juan M Barros Dios; Alberto Ruano Raviña; Jack Siemiatycki; Anita Koushik; Philip Lazarus; Ana Fernández-Somoano; Adonina Tardon; Loic Le Marchand; Hermann Brenner; Kai-Uwe Saum; Eric J Duell; Angeline S Andrew; Neonila Szeszenia-Dabrowska; Jolanta Lissowska; David Zaridze; Peter Rudnai; Eleonora Fabianova; Dana Mates; Lenka Foretova; Vladimir Janout; Vladimir Bencko; Ivana Holcatova; Angela Cecilia Pesatori; Dario Consonni; Ann Olsson; Kurt Straif; Rayjean J Hung Journal: Int J Cancer Date: 2017-02-27 Impact factor: 7.396
Authors: Maria Teresa Landi; Nilanjan Chatterjee; Kai Yu; Lynn R Goldin; Alisa M Goldstein; Melissa Rotunno; Lisa Mirabello; Kevin Jacobs; William Wheeler; Meredith Yeager; Andrew W Bergen; Qizhai Li; Dario Consonni; Angela C Pesatori; Sholom Wacholder; Michael Thun; Ryan Diver; Martin Oken; Jarmo Virtamo; Demetrius Albanes; Zhaoming Wang; Laurie Burdette; Kimberly F Doheny; Elizabeth W Pugh; Cathy Laurie; Paul Brennan; Rayjean Hung; Valerie Gaborieau; James D McKay; Mark Lathrop; John McLaughlin; Ying Wang; Ming-Sound Tsao; Margaret R Spitz; Yufei Wang; Hans Krokan; Lars Vatten; Frank Skorpen; Egil Arnesen; Simone Benhamou; Christine Bouchard; Andres Metspalu; Andres Metsapalu; Tonu Vooder; Mari Nelis; Kristian Välk; John K Field; Chu Chen; Gary Goodman; Patrick Sulem; Gudmar Thorleifsson; Thorunn Rafnar; Timothy Eisen; Wiebke Sauter; Albert Rosenberger; Heike Bickeböller; Angela Risch; Jenny Chang-Claude; H Erich Wichmann; Kari Stefansson; Richard Houlston; Christopher I Amos; Joseph F Fraumeni; Sharon A Savage; Pier Alberto Bertazzi; Margaret A Tucker; Stephen Chanock; Neil E Caporaso Journal: Am J Hum Genet Date: 2009-10-15 Impact factor: 11.025
Authors: Preetha Rajaraman; Beatrice S Melin; Zhaoming Wang; Roberta McKean-Cowdin; Dominique S Michaud; Sophia S Wang; Melissa Bondy; Richard Houlston; Robert B Jenkins; Margaret Wrensch; Meredith Yeager; Anders Ahlbom; Demetrius Albanes; Ulrika Andersson; Laura E Beane Freeman; Julie E Buring; Mary Ann Butler; Melissa Braganza; Tania Carreon; Maria Feychting; Sarah J Fleming; Susan M Gapstur; J Michael Gaziano; Graham G Giles; Goran Hallmans; Roger Henriksson; Judith Hoffman-Bolton; Peter D Inskip; Christoffer Johansen; Cari M Kitahara; Mark Lathrop; Chenwei Liu; Loic Le Marchand; Martha S Linet; Stefan Lonn; Ulrike Peters; Mark P Purdue; Nathaniel Rothman; Avima M Ruder; Marc Sanson; Howard D Sesso; Gianluca Severi; Xiao-Ou Shu; Matthias Simon; Meir Stampfer; Victoria L Stevens; Kala Visvanathan; Emily White; Alicja Wolk; Anne Zeleniuch-Jacquotte; Wei Zheng; Paul Decker; Victor Enciso-Mora; Brooke Fridley; Yu-Tang Gao; Matthew Kosel; Daniel H Lachance; Ching Lau; Terri Rice; Anthony Swerdlow; Joseph L Wiemels; John K Wiencke; Sanjay Shete; Yong-Bing Xiang; Yuanyuan Xiao; Robert N Hoover; Joseph F Fraumeni; Nilanjan Chatterjee; Patricia Hartge; Stephen J Chanock Journal: Hum Genet Date: 2012-08-11 Impact factor: 4.132
Authors: Ulrike Peters; Shuo Jiao; Fredrick R Schumacher; Carolyn M Hutter; Aaron K Aragaki; John A Baron; Sonja I Berndt; Stéphane Bézieau; Hermann Brenner; Katja Butterbach; Bette J Caan; Peter T Campbell; Christopher S Carlson; Graham Casey; Andrew T Chan; Jenny Chang-Claude; Stephen J Chanock; Lin S Chen; Gerhard A Coetzee; Simon G Coetzee; David V Conti; Keith R Curtis; David Duggan; Todd Edwards; Charles S Fuchs; Steven Gallinger; Edward L Giovannucci; Stephanie M Gogarten; Stephen B Gruber; Robert W Haile; Tabitha A Harrison; Richard B Hayes; Brian E Henderson; Michael Hoffmeister; John L Hopper; Thomas J Hudson; David J Hunter; Rebecca D Jackson; Sun Ha Jee; Mark A Jenkins; Wei-Hua Jia; Laurence N Kolonel; Charles Kooperberg; Sébastien Küry; Andrea Z Lacroix; Cathy C Laurie; Cecelia A Laurie; Loic Le Marchand; Mathieu Lemire; David Levine; Noralane M Lindor; Yan Liu; Jing Ma; Karen W Makar; Keitaro Matsuo; Polly A Newcomb; John D Potter; Ross L Prentice; Conghui Qu; Thomas Rohan; Stephanie A Rosse; Robert E Schoen; Daniela Seminara; Martha Shrubsole; Xiao-Ou Shu; Martha L Slattery; Darin Taverna; Stephen N Thibodeau; Cornelia M Ulrich; Emily White; Yongbing Xiang; Brent W Zanke; Yi-Xin Zeng; Ben Zhang; Wei Zheng; Li Hsu Journal: Gastroenterology Date: 2012-12-22 Impact factor: 22.682
Authors: Michael A James; Weidong Wen; Yian Wang; Lauren A Byers; John V Heymach; Kevin R Coombes; Luc Girard; John Minna; Ming You Journal: PLoS One Date: 2012-06-04 Impact factor: 3.240
Authors: Christopher I Amos; Joe Dennis; Zhaoming Wang; Jinyoung Byun; Fredrick R Schumacher; Simon A Gayther; Graham Casey; David J Hunter; Thomas A Sellers; Stephen B Gruber; Alison M Dunning; Kyriaki Michailidou; Laura Fachal; Kimberly Doheny; Amanda B Spurdle; Yafang Li; Xiangjun Xiao; Jane Romm; Elizabeth Pugh; Gerhard A Coetzee; Dennis J Hazelett; Stig E Bojesen; Charlisse Caga-Anan; Christopher A Haiman; Ahsan Kamal; Craig Luccarini; Daniel Tessier; Daniel Vincent; François Bacot; David J Van Den Berg; Stefanie Nelson; Stephen Demetriades; David E Goldgar; Fergus J Couch; Judith L Forman; Graham G Giles; David V Conti; Heike Bickeböller; Angela Risch; Melanie Waldenberger; Irene Brüske-Hohlfeld; Belynda D Hicks; Hua Ling; Lesley McGuffog; Andrew Lee; Karoline Kuchenbaecker; Penny Soucy; Judith Manz; Julie M Cunningham; Katja Butterbach; Zsofia Kote-Jarai; Peter Kraft; Liesel FitzGerald; Sara Lindström; Marcia Adams; James D McKay; Catherine M Phelan; Sara Benlloch; Linda E Kelemen; Paul Brennan; Marjorie Riggan; Tracy A O'Mara; Hongbing Shen; Yongyong Shi; Deborah J Thompson; Marc T Goodman; Sune F Nielsen; Andrew Berchuck; Sylvie Laboissiere; Stephanie L Schmit; Tameka Shelford; Christopher K Edlund; Jack A Taylor; John K Field; Sue K Park; Kenneth Offit; Mads Thomassen; Rita Schmutzler; Laura Ottini; Rayjean J Hung; Jonathan Marchini; Ali Amin Al Olama; Ulrike Peters; Rosalind A Eeles; Michael F Seldin; Elizabeth Gillanders; Daniela Seminara; Antonis C Antoniou; Paul D P Pharoah; Georgia Chenevix-Trench; Stephen J Chanock; Jacques Simard; Douglas F Easton Journal: Cancer Epidemiol Biomarkers Prev Date: 2016-10-03 Impact factor: 4.254
Authors: Jinyoung Byun; Younghun Han; Yafang Li; Jun Xia; Erping Long; Jiyeon Choi; Xiangjun Xiao; Meng Zhu; Wen Zhou; Ryan Sun; Yohan Bossé; Zhuoyi Song; Ann Schwartz; Christine Lusk; Thorunn Rafnar; Kari Stefansson; Tongwu Zhang; Wei Zhao; Rowland W Pettit; Yanhong Liu; Xihao Li; Hufeng Zhou; Kyle M Walsh; Ivan Gorlov; Olga Gorlova; Dakai Zhu; Susan M Rosenberg; Susan Pinney; Joan E Bailey-Wilson; Diptasri Mandal; Mariza de Andrade; Colette Gaba; James C Willey; Ming You; Marshall Anderson; John K Wiencke; Demetrius Albanes; Stephan Lam; Adonina Tardon; Chu Chen; Gary Goodman; Stig Bojeson; Hermann Brenner; Maria Teresa Landi; Stephen J Chanock; Mattias Johansson; Thomas Muley; Angela Risch; H-Erich Wichmann; Heike Bickeböller; David C Christiani; Gad Rennert; Susanne Arnold; John K Field; Sanjay Shete; Loic Le Marchand; Olle Melander; Hans Brunnstrom; Geoffrey Liu; Angeline S Andrew; Lambertus A Kiemeney; Hongbing Shen; Shanbeh Zienolddiny; Kjell Grankvist; Mikael Johansson; Neil Caporaso; Angela Cox; Yun-Chul Hong; Jian-Min Yuan; Philip Lazarus; Matthew B Schabath; Melinda C Aldrich; Alpa Patel; Qing Lan; Nathaniel Rothman; Fiona Taylor; Linda Kachuri; John S Witte; Lori C Sakoda; Margaret Spitz; Paul Brennan; Xihong Lin; James McKay; Rayjean J Hung; Christopher I Amos Journal: Nat Genet Date: 2022-08-01 Impact factor: 41.307
Authors: Wenjun Yang; Hongliang Liu; Ruoxin Zhang; Jennifer A Freedman; Younghun Han; Rayjean J Hung; Yonathan Brhane; John McLaughlin; Paul Brennan; Heike Bickeboeller; Albert Rosenberger; Richard S Houlston; Neil E Caporaso; Maria Teresa Landi; Irene Brueske; Angela Risch; David C Christiani; Christopher I Amos; Xiaoxin Chen; Steven R Patierno; Qingyi Wei Journal: NPJ Precis Oncol Date: 2022-06-30
Authors: Hang Li; Jun Che; Mian Jiang; Ming Cui; Guoxing Feng; Jiali Dong; Shuqin Zhang; Lu Lu; Weili Liu; Saijun Fan Journal: Cell Commun Signal Date: 2020-09-17 Impact factor: 5.712
Authors: Albert Rosenberger; Nils Muttray; Rayjean J Hung; David C Christiani; Neil E Caporaso; Geoffrey Liu; Stig E Bojesen; Loic Le Marchand; Demetrios Albanes; Melinda C Aldrich; Adonina Tardon; Guillermo Fernández-Tardón; Gad Rennert; John K Field; Michael P A Davies; Triantafillos Liloglou; Lambertus A Kiemeney; Philip Lazarus; Bernadette Wendel; Aage Haugen; Shanbeh Zienolddiny; Stephen Lam; Matthew B Schabath; Angeline S Andrew; Eric J Duell; Susanne M Arnold; Gary E Goodman; Chu Chen; Jennifer A Doherty; Fiona Taylor; Angela Cox; Penella J Woll; Angela Risch; Thomas R Muley; Mikael Johansson; Paul Brennan; Maria Teresa Landi; Sanjay S Shete; Christopher I Amos; Heike Bickeböller Journal: Eur J Med Res Date: 2022-01-31 Impact factor: 2.175