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Pancreas
Original article
Genome-wide association study of survival in patients with pancreatic adenocarcinoma
  1. Chen Wu1,2,
  2. Peter Kraft1,3,4,
  3. Rachael Stolzenberg-Solomon5,
  4. Emily Steplowski6,
  5. Michelle Brotzman7,
  6. Mousheng Xu1,
  7. Poorva Mudgal1,
  8. Laufey Amundadottir5,
  9. Alan A Arslan8,9,10,
  10. H Bas Bueno-de-Mesquita11,12,
  11. Myron Gross13,
  12. Kathy Helzlsouer14,15,
  13. Eric J Jacobs16,
  14. Charles Kooperberg17,
  15. Gloria M Petersen18,
  16. Wei Zheng19,
  17. Demetrius Albanes5,
  18. Marie-Christine Boutron-Ruault20,
  19. Julie E Buring21,22,
  20. Federico Canzian23,
  21. Guangwen Cao24,
  22. Eric J Duell25,
  23. Joanne W Elena26,
  24. J Michael Gaziano21,27,
  25. Edward L Giovannucci1,28,29,
  26. Goran Hallmans30,
  27. Amy Hutchinson31,
  28. David J Hunter1,28,
  29. Mazda Jenab32,
  30. Guoliang Jiang33,
  31. Kay-Tee Khaw34,
  32. Andrea LaCroix35,
  33. Zhaoshen Li36,
  34. Julie B Mendelsohn5,
  35. Salvatore Panico37,
  36. Alpa V Patel16,
  37. Zhi Rong Qian38,
  38. Elio Riboli39,
  39. Howard Sesso21,
  40. Hongbing Shen40,
  41. Xiao-Ou Shu19,
  42. Anne Tjonneland41,
  43. Geoffrey S Tobias5,
  44. Dimitrios Trichopoulos1,42,
  45. Jarmo Virtamo43,
  46. Kala Visvanathan44,
  47. Jean Wactawski-Wende45,
  48. Chengfeng Wang46,
  49. Kai Yu5,
  50. Anne Zeleniuch-Jacquotte9,10,
  51. Stephen Chanock5,
  52. Robert Hoover5,
  53. Patricia Hartge5,
  54. Charles S Fuchs29,38,
  55. Dongxin Lin2,
  56. Brian M Wolpin29,38
  1. 1Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  2. 2State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  3. 3Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA
  4. 4Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  5. 5Division of Cancer Epidemiology and Genetics, Department Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  6. 6Information Management Services, Silver Spring, Maryland, USA
  7. 7Westat, Inc., Rockville, Maryland, USA
  8. 8Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA
  9. 9Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA
  10. 10New York University Cancer Institute, New York, New York, USA
  11. 11National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  12. 12Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands
  13. 13Department of Laboratory Medicine/Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
  14. 14Prevention and Research Center, Mercy Medical Center, Baltimore, Maryland, USA
  15. 15Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
  16. 16Department of Epidemiology, American Cancer Society, Atlanta, Georgia, USA
  17. 17Program in Biostatistics and Biomathematics, Division of Public Health, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  18. 18Department of Health Sciences Research, Mayo Clinic, Rochester, Minneapolis, USA
  19. 19Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA
  20. 20Inserm (Institut National de la Sante et de la Recherche Medicale) and Institut Gustave Roussy, Villejuif, France
  21. 21Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  22. 22Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts, USA
  23. 23Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  24. 24Department of Epidemiology, Second Military Medical University, Shanghai, China
  25. 25Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
  26. 26Division of Cancer Control and Population Science, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  27. 27Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA
  28. 28Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA
  29. 29Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  30. 30Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden
  31. 31Core Genotyping Facility, SAIC-Frederick Inc., NCI-Frederick, Frederick, Maryland, USA
  32. 32International Agency for Research on Cancer, Lyon, France
  33. 33Department of Radiation Oncology, Cancer Hospital, Fudan University, Shanghai, China
  34. 34Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
  35. 35Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  36. 36Department of Gastroenterology, First Affiliated Hospital, Second Military Medical University, Shanghai, China
  37. 37Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
  38. 38Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  39. 39Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  40. 40Department of Epidemiology and Biostatistics, Cancer Center, Nanjing Medical University, Nanjing, China
  41. 41Danish Cancer Society Research Center, Copenhagen, Denmark
  42. 42Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
  43. 43Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
  44. 44Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
  45. 45Department of Social and Preventive Medicine, University at Buffalo, SUNY, Buffalo, New York, USA
  46. 46Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  1. Correspondence to Dr Brian Wolpin, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; bwolpin{at}partners.orgDr Dongxin Lin, State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China; lindx72@cicams.ac.cn

Abstract

Background and objective Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.

Methods We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10−5) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).

Results In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10−7), rs981621 (p=1.65×10−7) and rs16861827 (p=3.75×10−7), respectively. 131 SNPs with p≤10−5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10−7) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis.

Conclusions Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

  • Cancer Genetics
  • Molecular Epidemiology
  • Pancreatic Cancer

https://doi.org/10.1136/gutjnl-2012-303477

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