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Escala-Garcia, M., Abraham, J., Andrulis, I.L. et al. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis. Nat Commun 11, 312 (2020). https://doi.org/10.1038/s41467-019-14100-6

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

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Author: Escala-Garcia, Maria1; Abraham, Jean2,3,4,5; Andrulis, Irene L.6,7;
Anton-Culver, Hoda8; Arndt, Volker9; Ashworth, Alan10; Auer, Paul L.11,12; Auvinen, Paivi13,14,15; Beckmann, Matthias W.16; Beesley, Jonathan17; Behrens, Sabine18; Benitez, Javier19,20; Bermisheva, Marina21; Blomqvist, Carl22,23; Blot, William24,25; Bogdanova, Natalia V.26,27,28; Bojesen, Stig E.29,30,31; Bolla, Manjeet K.32; Borresen-Dale, Anne-Lise33,34; Brauch, Hiltrud35,36,37; Brenner, Hermann9,37,38,39; Brucker, Sara Y.40; Burwinkel, Barbara41,42; Caldas, Carlos43,44,45; Canzian, Federico46; Chang-Claude, Jenny18,47; Chanock, Stephen J.48; Chin, Suet-Feung49; Clarke, Christine L.50; Couch, Fergus J.51; Cox, Angela52; Cross, Simon S.53; Czene, Kamila54; Daly, Mary B.55; Dennis, Joe32; Devilee, Peter56,57; Dunn, Janet A.58; Dunning, Alison M.2; Dwek, Miriam59; Earl, Helena M.4,5,60; Eccles, Diana M.61; Eliassen, A. Heather62,63; Ellberg, Carolina64; Evans, D. Gareth65,66,67; Fasching, Peter A.16,68; Figueroa, Jonine48,69,70; Flyger, Henrik71; Gago-Dominguez, Manuela72,73; Gapstur, Susan M.74; Garcia-Closas, Montserrat48,75; Garcia-Saenz, Jose A.76; Gaudet, Mia M.74; George, Angela75; Giles, Graham G.77,78,79; Goldgar, David E.80; Gonzalez-Neira, Anna19; Grip, Mervi81; Guenel, Pascal82; Guo, Qi83; Haiman, Christopher A.84; Hakansson, Niclas85; Hamann, Ute86; Harrington, Patricia A.2; Hiller, Louise58; Hooning, Maartje J.87; Hopper, John L.78; Howell, Anthony88; Huang, Chiun-Sheng89,90; Huang, Guanmengqian86; Hunter, David J.63,91,92; Jakubowska, Anna93,94; John, Esther M.95; Kaaks, Rudolf18; Kapoor, Pooja Middha18,96; Keeman, Renske1; Kitahara, Cari M.97; Koppert, Linetta B.98; Kraft, Peter63,91; Kristensen, Vessela N.33,34; Lambrechts, Diether99,100; Le Marchand, Loic101; Lejbkowicz, Flavio102,103; Lindblom, Annika104,105; Lubinski, Jan93; Mannermaa, Arto15,106,107; Manoochehri, Mehdi86; Manoukian, Siranoush108; Margolin, Sara109,110; Martinez, Maria Elena73,111; Maurer, Tabea47; Mavroudis, Dimitrios112; Meindl, Alfons113; Milne, Roger L.77,78,114; Mulligan, Anna Marie115,116; Neuhausen, Susan L.117; Nevanlinna, Heli118; Newman, William G.65,66; Olshan, Andrew F.119; Olson, Janet E.; Olsson, Hakan64; Orr, Nick120; Peterlongo, Paolo121; Petridis, Christos122; Prentice, Ross L.11; Presneau, Nadege59; Punie, Kevin123; Ramachandran, Dhanya27; Rennert, Gad102,103; Romero, Atocha124; Sachchithananthan, Mythily50; Saloustros, Emmanouil125; Sawyer, Elinor J.122; Schmutzler, Rita K.126,127; Schwentner, Lukas128; Scott, Christopher; Simard, Jacques129; Sohn, Christof130; Southey, Melissa C.114,131; Swerdlow, Anthony J.75,132; Tamimi, Rulla M.62,63,91; Tapper, William J.133; Teixeira, Manuel R.134,135; Terry, Mary Beth136; Thorne, Heather137,138; Tollenaar, Rob A. E. M.139; Tomlinson, Ian140,141,142; Troester, Melissa A.119; Truong, Therese82; Turnbull, Clare75; Vachon, Celine M.; van der Kolk, Lizet E.143; Wang, Qin32; Winqvist, Robert144,145; Wolk, Alicja85,146; Yang, Xiaohong R.48; Ziogas, Argyrios8; Pharoah, Paul D. P.2,32; Hall, Per54,109; Wessels, Lodewyk F. A.147,148; Chenevix-Trench, Georgia17; Bader, Gary D.7,149; Doerk, Thilo27; Easton, Douglas F.2,32; Canisius, Sander1,147; Schmidt, Marjanka K.1,150
Organizations: 1Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Divi Mol Pathol, Amsterdam, Netherlands.
2Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England.
3Cambridge Expt Canc Med Ctr, Cambridge, England.
4Univ Cambridge NHS Fdn Hosp, NIHR Cambridge Biomed Res Ctr, Cambridge, England.
5Univ Cambridge NHS Fdn Hosp, Cambridge Breast Unit, Cambridge, England.
6Lunenfeld Tanenbaum Res Inst Mt Sinai Hosp, Fred A Litwin Ctr Canc Genet, Toronto, ON, Canada.
7Univ Toronto, Dept Mol Genet, Toronto, ON, Canada.
8Univ Calif Irvine, Genet Epidemiol Res Inst, Dept Epidemiol, Irvine, CA USA.
9German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
10Univ Calif San Francisco, UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA.
11Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA USA.
12Univ Wisconsin Milwaukee, Zilber Sch Publ Hlth, Milwaukee, WI USA.
13Kuopio Univ Hosp, Canc Ctr, Kuopio, Finland.
14Univ Eastern Finland, Inst Clin Med, Oncol, Kuopio, Finland.
15Univ Eastern Finland, Translat Canc Res Area, Kuopio, Finland.
16Friedrich Alexander Univ Erlangen Nuremberg, Univ Hosp Erlangen, Comprehens Canc Ctr ER EMN, Dept Gynecol & Obstet, Erlangen, Germany.
17QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia.
18German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany.
19Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Programme, Madrid, Spain.
20Biomed Network Rare Dis CIBERER, Madrid, Spain.
21Ufa Sci Ctr Russian Acad Sci, Inst Biochem & Genet, Ufa, Russia.
22Univ Helsinki, Helsinki Univ Hosp, Dept Oncol, Helsinki, Finland.
23Orebro Univ Hosp, Dept Oncol, Orebro, Sweden.
24Vanderbilt Univ Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr, Dept Med,Div Epidemiol, Nashville, TN USA.
25Int Epidemiol Inst, Rockville, MD USA.
26Hannover Med Sch, Dept Radiat Oncol, Hannover, Germany.
27Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany.
28NN Alexandrov Res Inst Oncol & Med Radiol, Minsk, BELARUS.
29Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Copenhagen Gen Populat Study, Herlev, Denmark.
30Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Clin Biochem, Herlev, Denmark.
31Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark.
32Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Publ Hlth & Primary Care, Cambridge, England.
33Oslo Univ Hosp Radiumhosp, Inst Canc Res, Dept Canc Genet, Oslo, Norway.
34Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
35Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany.
36Univ Tubingen, iFIT Cluster Excellence, Tubingen, Germany.
37German Canc Consortium DKTK, German Canc Res Ctr DKFZ, Heidelberg, Germany.
38Natl Ctr Tumor Dis NCT, Heidelberg, Germany.
39German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.
40Univ Tubingen, Dept Gynecol & Obstet, Tubingen, Germany.
41German Canc Res Ctr, Mol Epidemiol Grp, C080, Heidelberg, Germany.
42Heidelberg Univ, Univ Womens Clin Heidelberg, Mol Biol Breast Canc, Heidelberg, Germany.
43Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Dept Oncol, Cambridge, England.
44CRUK Cambridge Canc Ctr, Breast Canc Programme, Cambridge, England.
45Cambridge Univ Hosp NHS Fdn Trust, NIHR Biomed Res Ctr, Cambridge, England.
46German Canc Res Ctr, Gen Epidemiol Grp, Heidelberg, Germany.
47Univ Med Ctr Hamburg Eppendorf, Univ Canc Ctr Hamburg UCCH, Canc Epidemiol Grp, Hamburg, Germany.
48Natl Canc Inst, Natl Inst Hlth, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD USA.
49Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England.
50Univ Sydney, Westmead Inst Med Res, Sydney, NSW, Australia.
51Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
52Univ Sheffield, Sheffield Inst Nucle Acids SInFoNiA, Dept Oncol & Metab, Sheffield, S Yorkshire, England.
53Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England.
54Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
55Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA USA.
56Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands.
57Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands.
58Univ Warwick, Warwick Clin Trials Unit, Coventry, W Midlands, England.
59Univ Westminster, Fac Sci & Technol, Dept Biomed Sci, London, England.
60Univ Cambridge, Dept Oncol, Cambridge, England.
61Univ Southampton, Fac Med, Canc Sci Acad Unit, Southampton, Hants, England.
62Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA USA.
63Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA.
64Lund Univ, Dept Canc Epidemiol Clin Sci, Lund, Sweden.
65Univ Manchester, Manchester Acad Hlth Sci Ctr, Fac Biol Med & Hlth, Sch Biol Sci,Div Evolut & Genom Med, Manchester, Lancs, England.
66Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester Ctr Genom Med, St Marys Hosp,Genom Med, Manchester, Lancs, England.
67Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, NIHR Manchester Biomed Res Ctr, Manchester, Lancs, England.
68Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Hematol & Oncol, Los Angeles, CA USA.
69Univ Edinburgh Med Sch, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland.
70Canc Res UK Edinburgh Ctr, Edinburgh, Midlothian, Scotland.
71Copenhagen Univ Hosp, Herlev & Gentofte Hosp, Dept Breast Surg, Herlev, Denmark.
72Complejo Hospitalario Univ Santiago, SERGAS, Inst Invest Sanitaria Santiago Compostela IDIS, Galician Fdn Genom Med,Genom Med Grp, Santiago De Compostela, Spain.
73Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA.
74Amer Canc Soc, Epidemiol Res Program, Atlanta, GA USA.
75Inst Canc Res, Div Genet & Epidemiol, London, England.
76Hosp Clino San Carlos, Inst Invest Sanitaria San Carlos IdISSC, Ctr Invest Biomed Red Canc CIBERONC, Madrid, Spain.
77Canc Council Victoria, Canc Epidemiol Div, Melbourne, Vic, Australia.
78Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia.
79Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic, Australia.
80Univ Utah Sch Med Salt, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT USA.
81Univ Oulu, Oulu Univ Hosp, Dept Surg, Oulu, Finland.
82Univ Paris Sud, INSERM, Univ Paris Saclay, Ctr Res Epidemiol & Populat Hlth CESP,Canc & Envi, Villejuif, France.
83Univ Cambridge, Dept Publ Hlth & Primary Care, Cardiovasc Epidemiol Unit, Cambridge, England.
84Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA.
85Karolinska Inst, Inst Environm Med, Stockholm, Sweden.
86German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany.
87Erasmus MC Canc Inst, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands.
88Univ Manchester, Div Canc Sci, Manchester, Lancs, England.
89Natl Taiwan Univ Hosp, Dept Surg, Taipei, Taiwan.
90Natl Taiwan Univ Coll Med, Taipei, Taiwan.
91Harvard TH Chan Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA USA.
92Univ Oxford, Nuffield Dept Populat Hlth, Oxford, England.
93Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland.
94Pomeranian Med Univ, Independent Lab Mol Biol & Genet Diagnost, Szczecin, Poland.
95Stanford Univ Sch Med, Stanford Canc Inst, Dept Med, Div Oncol, Stanford, CA USA.
96Heidelberg Univ, Fac Med, Heidelberg, Germany.
97Natl Canc Inst, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD USA.
98Erasmus MC Canc Inst, Family Canc Clin, Dept Surg Oncol, Rotterdam, Netherlands.
99VIB Ctr Canc Biol, VIB, Leuven, Belgium.
100Univ Leuven, Lab Translat Genet, Dept Human Genet, Leuven, Belgium.
101Univ Hawaii Canc Ctr, Epidemiol Program, Honolulu, HI USA.
102Clalit Natl Canc Control Ctr, Technion Fac Med, Haifa, Israel.
103Carmel Hosp, Haifa, Israel.
104Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
105Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.
106Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland.
107Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, Kuopio, Finland.
108Fdn IRCCS Ist Nazl Tumori Milano INT, Dept Med Oncol & Hematol, Unit Med Genet, Milan, Italy.
109Ssdersjukhuset, Dept Oncol, Stockholm, Sweden.
110Karolinska Inst, Ssdersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
111Univ Calif San Diego, Dept Family Med & Publ Hlth, La Jolla, CA USA.
112Univ Hosp Herakl, Dept Med Oncol, Iraklion, Greece.
113Ludwig Maximilian Univ Munich, Dept Gynecol & Obstet, Munich, Germany.
114Monash Univ, Sch Clin Sci Monash Hlth, Precis Med, Clayton, Vic, Australia.
115Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
116Univ Hlth Network, Lab Med Program, Toronto, ON, Canada.
117Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA.
118Univ Helsinki, Helsinki Univ Hosp, Dept Obstet & Gynecol, Helsinki, Finland.
119Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Epidemiol, Chapel Hill, NC USA.
120Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland.
121Inst Mol Oncol, IFOM FIRC Italian Fdn Canc Research, Genome Diagnost Program, Milan, Italy.
122Guys Hosp, Kings Coll London, Res Oncol, London, England.
123Univ Hosp Leuven, Leuven Canc Inst, Leuven Multidisciplinary Breast Ctr, Dept Oncol, Leuven, Belgium.
124Hosp Univ Puerta Hierro, Med Oncol Dept, Madrid, Spain.
125Univ Hosp Larissa, Dept Oncol, Larisa, Greece.
126Univ Hosp Cologne, Ctr Hereditary Breast & Ovarian Canc, Cologne, Germany.
127Univ Cologne, Ctr Mol Med Cologne CMMC, Cologne, Germany.
128Univ Hosp Ulm, Dept Gynaecol & Obstet, Ulm, Germany.
129Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Gen Ctr, Quebec City, PQ, Canada.
130Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany.
131Univ Melbourne, Dept Clin Pathol, Melbourne, Vic, Australia.
132Inst Canc Res, Div Breast Canc Res, London, England.
133Univ Southampton, Fac Med, Southampton, Hants, England.
134Portuguese Oncol Inst, Dept Genet, Porto, Portugal.
135Univ Porto, Biomed Sci Inst ICBAS, Porto, Portugal.
136Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA.
137Peter MacCallum Canc Ctr, Melbourne, Vic, Australia.
138Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia.
139Leiden Univ Med Ctr, Dept Surg, Leiden, Netherlands.
140Univ Birmingham, Inst Canc & Genom Sci, Birmingham, W Midlands, England.
141Univ Oxford, Oxford NIHR Biomed Res Ctr, Oxford, England.
142Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.
143Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands.
144Univ Oulu, Lab Canc Genet & Tumor Biol, Canc & Translat Med Res Unit, Bioctr Oulu, Oulu, Finland.
145Northern Finland Lab Ctr Oulu, Lab Canc Genet & Tumor Biol, Oulu, Finland.
146Uppsala Univ, Dept Surg Sci, Uppsala, Sweden.
147Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Mol Carcinogenesis, Amsterdam, Netherlands.
148Delft Univ Technol, Fac EEMCS, Delft, Netherlands.
149Univ Toronto, Donnelly Ctr, Toronto, ON, Canada.
150Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020041516657
Language: English
Published: Springer Nature, 2020
Publish Date: 2020-04-15
Description:

Abstract

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 11
Article number: 312
DOI: 10.1038/s41467-019-14100-6
OADOI: https://oadoi.org/10.1038/s41467-019-14100-6
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Subjects:
Article
Funding: The OBCS was supported by research grants from the Finnish Cancer Foundation, the Academy of Finland (grant number 250083, 122715 and Center of Excellence grant number 251314), the Finnish Cancer Foundation, the Sigrid Juselius Foundation, the University of Oulu, the University of Oulu Support Foundation and the special Governmental EVO funds for Oulu University Hospital-based research activities.
Academy of Finland Grant Number: 122715
251314
Detailed Information: 122715 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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