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López de Maturana E, Rodríguez JA, Alonso L, et al. A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer. Genome Med. 2021;13(1):15doi: 10.1186/s13073-020-00816-4.
López de Maturana, E., Rodríguez, J. A., Alonso, L., Lao, O., Molina-Montes, E., Martín-Antoniano, I. A., Gómez-Rubio, P., Lawlor, R., Carrato, A., Hidalgo, M., Iglesias, M., Molero, X., Löhr, M., Michalski, C., Perea, J., O'Rorke, M., Barberà, V. M., Tardón, A., Farré, A., Muñoz-Bellvís, L., Crnogorac-Jurcevic, T., Domínguez-Muñoz, E., Gress, T., Greenhalf, W., Sharp, L., Arnes, L., Cecchini, L., Balsells, J., Costello, E., Ilzarbe, L., Kleeff, J., Kong, B., Márquez, M., Mora, J., O'Driscoll, D., Scarpa, A., Ye, W., Yu, J., García-Closas, M., Kogevinas, M., Rothman, N., Silverman, D. T., Albanes, D., Arslan, A. A., Beane-Freeman, L., Bracci, P. M., Brennan, P., Bueno-de-Mesquita, B., Buring, J., Canzian, F., Du, M., Gallinger, S., Gaziano, J. M., Goodman, P. J., Gunter, M., LeMarchand, L., Li, D., Neale, R. E., Peters, U., Petersen, G. M., Risch, H. A., Sánchez, M. J., Shu, X. O., Thornquist, M. D., Visvanathan, K., Zheng, W., Chanock, S. J., Easton, D., Wolpin, B. M., Stolzenberg-Solomon, R. Z., Klein, A. P., Amundadottir, L. T., Marti-Renom, M. A., Real, F. X., & Malats, N. (2021). A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer. Genome medicine, 13(1), 15. https://doi.org/10.1186/s13073-020-00816-4
López de Maturana, Evangelina, et al. "A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer." Genome medicine vol. 13,1 (2021): 15. doi: https://doi.org/10.1186/s13073-020-00816-4
López de Maturana E, Rodríguez JA, Alonso L, Lao O, Molina-Montes E, Martín-Antoniano IA, Gómez-Rubio P, Lawlor R, Carrato A, Hidalgo M, Iglesias M, Molero X, Löhr M, Michalski C, Perea J, O'Rorke M, Barberà VM, Tardón A, Farré A, Muñoz-Bellvís L, Crnogorac-Jurcevic T, Domínguez-Muñoz E, Gress T, Greenhalf W, Sharp L, Arnes L, Cecchini L, Balsells J, Costello E, Ilzarbe L, Kleeff J, Kong B, Márquez M, Mora J, O'Driscoll D, Scarpa A, Ye W, Yu J, García-Closas M, Kogevinas M, Rothman N, Silverman DT, Albanes D, Arslan AA, Beane-Freeman L, Bracci PM, Brennan P, Bueno-de-Mesquita B, Buring J, Canzian F, Du M, Gallinger S, Gaziano JM, Goodman PJ, Gunter M, LeMarchand L, Li D, Neale RE, Peters U, Petersen GM, Risch HA, Sánchez MJ, Shu XO, Thornquist MD, Visvanathan K, Zheng W, Chanock SJ, Easton D, Wolpin BM, Stolzenberg-Solomon RZ, Klein AP, Amundadottir LT, Marti-Renom MA, Real FX, Malats N. A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer. Genome Med. 2021 Feb 01;13(1):15. doi: 10.1186/s13073-020-00816-4. PMID: 33517887; PMCID: PMC7849104.
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Genome Med. 2021 Feb 01;13(1):15. doi: 10.1186/s13073-020-00816-4.

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

Genome medicine

Evangelina López de Maturana, Juan Antonio Rodríguez, Lola Alonso, Oscar Lao, Esther Molina-Montes, Isabel Adoración Martín-Antoniano, Paulina Gómez-Rubio, Rita Lawlor, Alfredo Carrato, Manuel Hidalgo, Mar Iglesias, Xavier Molero, Matthias Löhr, Christopher Michalski, José Perea, Michael O'Rorke, Victor Manuel Barberà, Adonina Tardón, Antoni Farré, Luís Muñoz-Bellvís, Tanja Crnogorac-Jurcevic, Enrique Domínguez-Muñoz, Thomas Gress, William Greenhalf, Linda Sharp, Luís Arnes, Lluís Cecchini, Joaquim Balsells, Eithne Costello, Lucas Ilzarbe, Jörg Kleeff, Bo Kong, Mirari Márquez, Josefina Mora, Damian O'Driscoll, Aldo Scarpa, Weimin Ye, Jingru Yu, Montserrat García-Closas, Manolis Kogevinas, Nathaniel Rothman, Debra T Silverman, Demetrius Albanes, Alan A Arslan, Laura Beane-Freeman, Paige M Bracci, Paul Brennan, Bas Bueno-de-Mesquita, Julie Buring, Federico Canzian, Margaret Du, Steve Gallinger, J Michael Gaziano, Phyllis J Goodman, Marc Gunter, Loic LeMarchand, Donghui Li, Rachael E Neale, Ulrika Peters, Gloria M Petersen, Harvey A Risch, Maria José Sánchez, Xiao-Ou Shu, Mark D Thornquist, Kala Visvanathan, Wei Zheng, Stephen J Chanock, Douglas Easton, Brian M Wolpin, Rachael Z Stolzenberg-Solomon, Alison P Klein, Laufey T Amundadottir, Marc A Marti-Renom, Francisco X Real, Núria Malats

Affiliations

  1. Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), C/Melchor Fernandez Almagro 3, 28029, Madrid, Spain.
  2. CIBERONC, Madrid, Spain.
  3. CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  4. ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy.
  5. Department of Oncology, Ramón y Cajal University Hospital, IRYCIS, Alcala University, Madrid, Spain.
  6. Madrid-Norte-Sanchinarro Hospital, Madrid, Spain.
  7. Weill Cornell Medicine, New York, USA.
  8. Hospital del Mar-Parc de Salut Mar, Barcelona, Spain.
  9. Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
  10. Universitat Autònoma de Barcelona and CIBEREHD, Barcelona, Spain.
  11. Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, Sweden.
  12. Department of Surgery, Technical University of Munich, Munich, Germany.
  13. Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-WittenberHalle (Saale), Halle, Germany.
  14. Department of Surgery, Hospital 12 de Octubre, and Department of Surgery and Health Research Institute, Fundación Jiménez Díaz, Madrid, Spain.
  15. Centre for Public Health, Queen's University Belfast, Belfast, UK.
  16. College of Public Health, The University of Iowa, Iowa City, IA, USA.
  17. Molecular Genetics Laboratory, General University Hospital of Elche, Elche, Spain.
  18. Department of Medicine, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
  19. CIBERESP, Madrid, Spain.
  20. Department of Gastroenterology and Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
  21. Department of Surgery, Hospital Universitario de Salamanca - IBSAL, Universidad de Salamanca, Salamanca, Spain.
  22. Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of London, London, UK.
  23. Department of Gastroenterology, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain.
  24. Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, Germany.
  25. Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
  26. National Cancer Registry Ireland and HRB Clinical Research Facility, University College Cork, Cork, Ireland.
  27. Newcastle University, Institute of Health & Society, Newcastle, UK.
  28. Centre for Stem Cell Research and Developmental Biology, University of Copenhagen, Copenhagen, Denmark.
  29. Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.
  30. Department of Systems Biology, Columbia University Medical Center, New York, NY, USA.
  31. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stokholm, Sweden.
  32. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  33. Institut Municipal d'Investigació Mèdica - Hospital del Mar, Centre de Recerca en Epidemiologia Ambiental (CREAL), Barcelona, Spain.
  34. Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA.
  35. Department of Environmental Medicine, New York University School of Medicine, New York, NY, USA.
  36. Department of Population Health, New York University School of Medicine, New York, NY, USA.
  37. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
  38. International Agency for Research on Cancer (IARC), Lyon, France.
  39. Deparment for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
  40. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, USA.
  41. Genomic Epidemiology Group, German Cancer Research Center (DKFZ, Heidelberg, Germany.
  42. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  43. Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  44. Departments of Medicine, Brigham and Women's Hospital, VA Boston and Harvard Medical School, Boston, MA, USA.
  45. SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  46. Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
  47. University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  48. Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
  49. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  50. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, USA.
  51. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
  52. Escuela Andaluza de Salud Pública (EASP), Granada, Spain.
  53. Instituto de Investigación Biosanitaria Granada, Granada, Spain.
  54. Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
  55. Universidad de Granada, Granada, Spain.
  56. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
  57. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  58. Department Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
  59. Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
  60. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  61. National Centre for Genomic Analysis (CNAG), Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra (UPF), ICREA, Baldiri Reixac 4, 08028, Barcelona, Spain. [email protected].
  62. Epithelial Carcinogenesis Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
  63. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
  64. Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), C/Melchor Fernandez Almagro 3, 28029, Madrid, Spain. [email protected].
  65. CIBERONC, Madrid, Spain. [email protected].

PMID: 33517887 PMCID: PMC7849104 DOI: 10.1186/s13073-020-00816-4

Abstract

BACKGROUND: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.

METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.

RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.

CONCLUSIONS: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Keywords: 3D genomic structure; Genetic susceptibility; Genome-wide association analysis; Local indices of genome spatial autocorrelation; Pancreatic cancer risk

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