A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer
Por:
de Maturana, E, Rodriguez, J, Alonso, L, Lao, O, Molina-Montes, E, Martin-Antoniano, I, Gomez-Rubio, P, Lawlor, R, Carrato, A, Hidalgo, M, Iglesias, M, Molero, X, Lohr, M, Michalski, C, Perea, J, O'Rorke, M, Barbera V, Tardon, A, Farre, A, Munoz-Bellvis, L, Crnogorac-Jurcevic, T, Dominguez-Munoz, E, Gress, T, Greenhalf, W, Sharp, L, Arnes, L, Cecchini, L, Balsells, J, Costello, E, Ilzarbe, L, Kleeff, J, Kong, B, Marquez, M, Mora, J, O'Driscoll, D, Scarpa, A, Ye, W, Yu, J, Garcia-Closas, M, Kogevinas, M, Rothman, N, Silverman, D, Albanes, D, Arslan, A, Beane-Freeman, L, Bracci, P, Brennan, P, Bueno-de-Mesquita, B, Buring, J, Canzian, F, Du, M, Gallinger, S, Gaziano, J, Goodman, P, Gunter, M, LeMarchand, L, Li, D, Neale, R, Peters, U, Petersen, G, Risch, H, Sanchez, M, Shu, X, Thornquist, M, Visvanathan, K, Zheng, W, Chanock, S, Easton, D, Wolpin, B, Stolzenberg-Solomon, R, Klein, A, Amundadottir, L, Marti-Renom, M, Real, F, Malats, N, PanGenEU Investigators and SBC EPICURO Investigators
Publicada:
1 feb 2021
Ahead of Print:
1 feb 2021
Resumen:
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.
Filiaciones:
de Maturana, E:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Rodriguez, J:
Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Barcelona, Spain
Alonso, L:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Lao, O:
Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Barcelona, Spain
Molina-Montes, E:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Martin-Antoniano, I:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Gomez-Rubio, P:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Lawlor, R:
Univ & Hosp Trust Verona, ARC Net Ctr Appl Res Canc, Verona, Italy
Univ & Hosp Trust Verona, Dept Pathol & Diagnost, Verona, Italy
Carrato, A:
Ciberonc, Madrid, Spain
Alcala Univ, Ramon y Cajal Univ Hosp, Dept Oncol, IRYCIS, Madrid, Spain
Hidalgo, M:
Madrid Norte Sanchinarro Hosp, Madrid, Spain
Weill Cornell Med, New York, NY USA
Iglesias, M:
Ciberonc, Madrid, Spain
Hosp del Mar Parc Salut Mar, Barcelona, Spain
Molero, X:
Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
CIBEREHD, Barcelona, Spain
Lohr, M:
Karolinska Inst, Gastroctr, Stockholm, Sweden
Univ Hosp, Stockholm, Sweden
Michalski, C:
Tech Univ Munich, Dept Surg, Munich, Germany
Martin Luther Univ Halle WittenberHalle Saale, Dept Visceral Vasc & Endocrine Surg, Halle, Germany
Perea, J:
Hosp 12 Octubre, Dept Surg, Madrid, Spain
Fdn Jimenez Diaz, Dept Surg, Madrid, Spain
Fdn Jimenez Diaz, Hlth Res Inst, Madrid, Spain
O'Rorke, M:
Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland
Univ Iowa, Coll Publ Hlth, Iowa City, IA USA
Barbera V:
Gen Univ Hosp Elche, Mol Genet Lab, Elche, Spain
Tardon, A:
Inst Univ Oncol Principado Asturias IUOPA, Inst Invest Sanitaria Principado Asturias ISPA, Dept Med, Oviedo, Spain
CIBERESP, Madrid, Spain
Farre, A:
Hosp Santa Creu & Sant Pau, Dept Gastroenterol & Clin Biochem, Barcelona, Spain
Munoz-Bellvis, L:
Ciberonc, Madrid, Spain
Univ Salamanca, Hosp Univ Salamanca IBSAL, Dept Surg, Salamanca, Spain
Crnogorac-Jurcevic, T:
Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England
Dominguez-Munoz, E:
Univ Clin Hosp Santiago de Compostela, Dept Gastroenterol, Santiago De Compostela, Spain
Gress, T:
Univ Hosp Giessen & Marburg, Dept Gastroenterol, Marburg, Germany
Greenhalf, W:
Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England
Sharp, L:
Univ Coll Cork, Natl Canc Registry Ireland, Cork, Ireland
Univ Coll Cork, HRB Clin Res Facil, Cork, Ireland
Newcastle Univ, Inst Hlth & Soc, Newcastle, England
Arnes, L:
Univ Copenhagen, Ctr Stem Cell Res & Dev Biol, Copenhagen, Denmark
Columbia Univ, Med Ctr, Dept Genet & Dev, New York, NY USA
Columbia Univ, Med Ctr, Dept Syst Biol, New York, NY USA
Cecchini, L:
Ciberonc, Madrid, Spain
Hosp del Mar Parc Salut Mar, Barcelona, Spain
Balsells, J:
Hosp Univ Vall dHebron, Vall dHebron Res Inst VHIR, Barcelona, Spain
Univ Autonoma Barcelona, Barcelona, Spain
CIBEREHD, Barcelona, Spain
Costello, E:
Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England
Ilzarbe, L:
Ciberonc, Madrid, Spain
Hosp del Mar Parc Salut Mar, Barcelona, Spain
Kleeff, J:
Tech Univ Munich, Dept Surg, Munich, Germany
Martin Luther Univ Halle WittenberHalle Saale, Dept Visceral Vasc & Endocrine Surg, Halle, Germany
Kong, B:
Tech Univ Munich, Dept Surg, Munich, Germany
Marquez, M:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Mora, J:
Hosp Santa Creu & Sant Pau, Dept Gastroenterol & Clin Biochem, Barcelona, Spain
O'Driscoll, D:
Univ Coll Cork, Natl Canc Registry Ireland, Cork, Ireland
Univ Coll Cork, HRB Clin Res Facil, Cork, Ireland
Scarpa, A:
Univ & Hosp Trust Verona, ARC Net Ctr Appl Res Canc, Verona, Italy
Univ & Hosp Trust Verona, Dept Pathol & Diagnost, Verona, Italy
Ye, W:
Karolinska Inst, Dept Med Epidemiol & Biostat, Stokholm, Sweden
Yu, J:
Karolinska Inst, Dept Med Epidemiol & Biostat, Stokholm, Sweden
Garcia-Closas, M:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Kogevinas, M:
CIBERESP, Madrid, Spain
Hosp del Mar, Ctr Recerca Epidemiol Ambiental CREAL, Inst Municipal Invest Med, Barcelona, Spain
Rothman, N:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Silverman, D:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Albanes, D:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Arslan, A:
NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA
NYU, Sch Med, Dept Environm Med, New York, NY USA
NYU, Sch Med, Dept Populat Hlth, New York, NY USA
Beane-Freeman, L:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Bracci, P:
Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA
Brennan, P:
Int Agcy Res Canc IARC, Lyon, France
Bueno-de-Mesquita, B:
Natl Inst Publ Hlth & Environm RIVM, Dept Determinants Chron Dis DCD, Bilthoven, Netherlands
Buring, J:
Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA
Canzian, F:
German Canc Res Ctr, Genom Epidemiol Grp, Heidelberg, Germany
Du, M:
Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA
Gallinger, S:
Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Populat Hlth Res, Toronto, ON, Canada
Gaziano, J:
Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA
Harvard Med Sch, Boston, MA 02115 USA
Goodman, P:
Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, 1124 Columbia St, Seattle, WA 98104 USA
Gunter, M:
Int Agcy Res Canc IARC, Lyon, France
LeMarchand, L:
Univ Hawaii, Ctr Canc, Canc Epidemiol Program, Honolulu, HI 96822 USA
Li, D:
Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA
Neale, R:
QIMR Berghofer Med Res Inst, Populat Hlth Dept, Brisbane, Qld, Australia
Peters, U:
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA
Petersen, G:
Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA
Risch, H:
Yale Sch Publ Hlth, Dept Chron Dis Epidemiol, New Haven, CT USA
Sanchez, M:
Escuela Andaluza Salud Publ EASP, Granada, Spain
Inst Invest Biosanitaria Granada, Granada, Spain
Ctr Invest Biomed Red Epidemiol & Salud Publ CIBE, Madrid, Spain
Univ Granada, Granada, Spain
Shu, X:
Vanderbilt Univ, Sch Med, VanderbiltIngram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA
Thornquist, M:
Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA
Visvanathan, K:
Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA
Zheng, W:
Vanderbilt Univ, Sch Med, VanderbiltIngram Canc Ctr, Div Epidemiol,Dept Med,Vanderbilt Epidemiol Ctr, Nashville, TN 37212 USA
Chanock, S:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Easton, D:
Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England
Wolpin, B:
Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
Stolzenberg-Solomon, R:
NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Klein, A:
Johns Hopkins Sch Med, Sidney Kimmel Comprehens Canc Ctr, Dept Oncol, Baltimore, MD USA
Amundadottir, L:
NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA
Marti-Renom, M:
Univ Pompeu Fabra UPF, Barcelona Inst Sci & Technol BIST, Natl Ctr Genom Anal CNAG, Ctr Genom Regulat CRG,ICREA, Baldiri Reixac 4, Barcelona 08028, Spain
Real, F:
Ciberonc, Madrid, Spain
Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain
Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain
Malats, N:
Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain
Ciberonc, Madrid, Spain
Green Published, Green Submitted, gold
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