Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response

Author:

Carreras-Torres Robert123ORCID,Kim Andre E.4ORCID,Lin Yi5ORCID,Díez-Obrero Virginia126ORCID,Bien Stephanie A.5ORCID,Qu Conghui5ORCID,Wang Jun4ORCID,Dimou Niki7ORCID,Aglago Elom K.7ORCID,Albanes Demetrius8ORCID,Arndt Volker9ORCID,Baurley James W.10ORCID,Berndt Sonja I.8ORCID,Bézieau Stéphane11ORCID,Bishop D. Timothy12ORCID,Bouras Emmanouil13ORCID,Brenner Hermann91415ORCID,Budiarto Arif10ORCID,Campbell Peter T.16ORCID,Casey Graham17ORCID,Chan Andrew T.18ORCID,Chang-Claude Jenny19ORCID,Chen Xuechen9ORCID,Conti David V.4ORCID,Dampier Christopher H.20ORCID,Devall Matthew A.M.17ORCID,Drew David A.21ORCID,Figueiredo Jane C.22ORCID,Gallinger Steven23ORCID,Giles Graham G.24ORCID,Gruber Stephen B.25ORCID,Gsur Andrea26ORCID,Gunter Marc J.7ORCID,Harrison Tabitha A.5ORCID,Hidaka Akihisa5ORCID,Hoffmeister Michael9ORCID,Huyghe Jeroen R.5ORCID,Jenkins Mark A.27ORCID,Jordahl Kristina M.5ORCID,Kawaguchi Eric4ORCID,Keku Temitope O.28ORCID,Kundaje Anshul29ORCID,Le Marchand Loic30ORCID,Lewinger Juan Pablo4ORCID,Li Li31ORCID,Mahesworo Bharuno10ORCID,Morrison John L.4ORCID,Murphy Neil7ORCID,Nan Hongmei32ORCID,Nassir Rami33ORCID,Newcomb Polly A.5ORCID,Obón-Santacana Mireia126ORCID,Ogino Shuji34353637ORCID,Ose Jennifer3839ORCID,Pai Rish K.40ORCID,Palmer Julie R.41ORCID,Papadimitriou Nikos7ORCID,Pardamean Bens10ORCID,Peoples Anita R.38ORCID,Pharoah Paul D.P.42ORCID,Platz Elizabeth A.43ORCID,Rennert Gad44ORCID,Ruiz-Narvaez Edward45ORCID,Sakoda Lori C.46ORCID,Scacheri Peter C.47ORCID,Schmit Stephanie L.4849ORCID,Schoen Robert E.50ORCID,Shcherbina Anna51ORCID,Slattery Martha L.52ORCID,Stern Mariana C.4ORCID,Su Yu-Ru5ORCID,Tangen Catherine M.53ORCID,Thomas Duncan C.4ORCID,Tian Yu1954ORCID,Tsilidis Konstantinos K.5556ORCID,Ulrich Cornelia M.3839ORCID,van Duijnhoven Fränzel J.B.57ORCID,Van Guelpen Bethany5859ORCID,Visvanathan Kala43ORCID,Vodicka Pavel60ORCID,Cenggoro Tjeng Wawan10ORCID,Weinstein Stephanie J.8ORCID,White Emily61ORCID,Wolk Alicja62ORCID,Woods Michael O.63ORCID,Hsu Li5ORCID,Peters Ulrike564ORCID,Moreno Victor12665ORCID,Gauderman W. James4ORCID

Affiliation:

1. 1Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

2. 2Oncology Data Analytics Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, Barcelona, Spain.

3. 3Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain.

4. 4Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California.

5. 5Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

6. 6Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.

7. 7Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.

8. 8Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

9. 9Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

10. 10Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.

11. 11Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.

12. 12Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.

13. 13Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

14. 14Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.

15. 15German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

16. 16Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.

17. 17Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia.

18. 18Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

19. 19Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

20. 20Department of General Surgery, University of Virginia School of Medicine, Charlottesville, Virginia.

21. 21Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

22. 22Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.

23. 23Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

24. 24Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

25. 25Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, California.

26. 26Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.

27. 27Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.

28. 28Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.

29. 29Department of Genetics, Department of Computer Science, Stanford University, Stanford, California.

30. 30University of Hawaii Cancer Center, Honolulu, Hawaii.

31. 31Department of Family Medicine, University of Virginia, Charlottesville, Virginia.

32. 32Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.

33. 33Department of Pathology, School of Medicine, Umm Al-Qura'a University, Saudi Arabia.

34. 34Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

35. 35Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

36. 36Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

37. 37Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

38. 38Huntsman Cancer Institute, Salt Lake City, Utah.

39. 39Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.

40. 40Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.

41. 41Slone Epidemiology Center at Boston University, Boston, Massachusetts.

42. 42Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

43. 43Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

44. 44Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.

45. 45Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.

46. 46Division of Research, Kaiser Permanente Northern California, Oakland, California.

47. 47Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.

48. 48Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.

49. 49Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, Ohio.

50. 50Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

51. 51Biomedical Informatics Program, Dept. of Biomedical Data Sciences, Stanford University, Stanford, California.

52. 52Department of Internal Medicine, University of Utah, Salt Lake City, Utah.

53. 53SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.

54. 54School of Public Health, Capital Medical University, Beijing, P.R. China.

55. 55Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.

56. 56Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

57. 57Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.

58. 58Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.

59. 59Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.

60. 60Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, and Biomedical Center, Medical Faculty, Pilsen, Czech Republic.

61. 61Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

62. 62Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

63. 63Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.

64. 64School of Public Health, University of Washington, Seattle, Washington.

65. 65Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.

Abstract

AbstractBackground:Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.Methods:A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.Results:Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09–1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07–1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33).Conclusions:Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response.Impact:These findings can guide potential prevention treatments.

Funder

National Institutes of Health

Cancer Research UK

Medical Research Council

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology,Epidemiology

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