TY - JOUR
T1 - The role of genetic breast cancer susceptibility variants as prognostic factors
AU - Fasching, Peter A.
AU - Pharoah, Paul D.P.
AU - Cox, Angela
AU - Nevanlinna, Heli
AU - Bojesen, Stig E.
AU - Karn, Thomas
AU - Broeks, Annegien
AU - Van Leeuwen, Flora E.
AU - Van't Veer, Laura J.
AU - Udo, Renate
AU - Dunning, Alison M.
AU - Greco, Dario
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Shah, Mitul
AU - Nordestgaard, Børge G.
AU - Flyger, Henrik
AU - Hopper, John L.
AU - Southey, Melissa C.
AU - Apicella, Carmel
AU - Garcia-Closas, Montserrat
AU - Sherman, Mark
AU - Lissowska, Jolanta
AU - Seynaeve, Caroline
AU - Huijts, Petra E.A.
AU - Tollenaar, Rob A.E.M.
AU - Ziogas, Argyrios
AU - Ekici, Arif B.
AU - Rauh, Claudia
AU - Mannermaa, Arto
AU - Kataja, Vesa
AU - Kosma, Veli Matti
AU - Hartikainen, Jaana M.
AU - Andrulis, Irene L.
AU - Ozcelik, Hilmi
AU - Mulligan, Anna Marie
AU - Glendon, Gord
AU - Hall, Per
AU - Czene, Kamila
AU - Liu, Jianjun
AU - Chang-Claude, Jenny
AU - Wang-Gohrke, Shan
AU - Eilber, Ursula
AU - Nickels, Stefan
AU - Dörk, Thilo
AU - Schiekel, Maria
AU - Bremer, Michael
AU - Park-Simon, Tjoung Won
AU - Giles, Graham G.
AU - Severi, Gianluca
AU - Baglietto, Laura
AU - Hooning, Maartje J.
AU - Martens, John W.M.
AU - Jager, Agnes
AU - Kriege, Mieke
AU - Lindblom, Annika
AU - Margolin, Sara
AU - Couch, Fergus J.
AU - Stevens, Kristen N.
AU - Olson, Janet E.
AU - Kosel, Matthew
AU - Cross, Simon S.
AU - Balasubramanian, Sabapathy P.
AU - Reed, Malcolm W.R.
AU - Miron, Alexander
AU - John, Esther M.
AU - Winqvist, Robert
AU - Pylkäs, Katri
AU - Jukkola-Vuorinen, Arja
AU - Kauppila, Saila
AU - Burwinkel, Barbara
AU - Marme, Frederik
AU - Schneeweiss, Andreas
AU - Sohn, Christof
AU - Chenevix-Trench, Georgia
AU - Lambrechts, Diether
AU - Dieudonne, Anne Sophie
AU - Hatse, Sigrid
AU - Van Limbergen, Erik
AU - Benitez, Javier
AU - Milne, Roger L.
AU - Zamora, M. Pilar
AU - Pérez, José Ignacio Arias
AU - Bonanni, Bernardo
AU - Peissel, Bernard
AU - Loris, Bernard
AU - Peterlongo, Paolo
AU - Rajaraman, Preetha
AU - Schonfeld, Sara J.
AU - Anton-Culver, Hoda
AU - Devilee, Peter
AU - Beckmann, Matthias W.
AU - Slamon, Dennis J.
AU - Phillips, Kelly Anne
AU - Figueroa, Jonine D.
AU - Humphreys, Manjeet K.
AU - Easton, Douglas F.
AU - Schmidt, Marjanka K.
N1 - Funding Information:
This work was supported by funding from the European Community’s Seventh Framework Programme under grant agreement -223175 (HEALTH-F2-2009-223175) (COGS). Co-ordination and genotyping in BCAC was funded by CR-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). D.F.E. is a Principal Research Fellow of CR-UK. The genotyping was supported by Cancer Research UK (C490/A10124) and (C1287/A12014). Funding of the constituent studies and data analysis was supported by the Cambridge Biomedical Research Centre, Cancer Research UK (C490/A10119). Other studies have been funded by the Dutch Cancer Society (grants NKI 2001-2423; NKI 2007-3839), the Dutch National Genomics Initiative, the Dutch Biobanking and Biomolecular Resources Research Infrastructure, the National Institutes of Health (NIH) National Cancer Institute (NCI) grant CA122340, NCI Recovery Act grant CA122340Z, NCI Specialized Program of Research Excellence (SPORE) in breast cancer CA116201, the ELAN research program, University Hospital Erlangen, the Deutsche Krebshilfe e. V. (70492), the state of Baden-Württemberg through the Medical Faculty of the University of Ulm (P.685), the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, the Associazione Italiana per la Ricerca sul Cancro (4017) and funds from Italian citizens who allocated the 5/1000 share of their tax payment in support of the Fonda-zione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects “5x1000”), the ‘Stichting tegen Kanker’ (232-2008 and 196-2010), the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland, the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Copenhagen University Hospital, Herlev Hospital, Rudolf Bartling Foundation, the National Breast Cancer Foundation of Australia, Cancer Australia, the National Health and Medical Research Council of Australia, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, the Cancer Foundation of Western Australia, the Victorian Health Promotion Foundation (Australia), the Breast Cancer Campaign (2004Nov49), Yorkshire Cancer Research (S295, S299 and core funding), the Dietmar-Hopp Foundation, the Helmholtz Society, the German Cancer Research Center (DKFZ), the Finnish Cancer Foundation, the Academy of Finland, the University of Oulu, the Oulu University Hospital, Biocenter Oulu; the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, the Nordic Cancer Union and the Sigrid Juse-lius Foundation; the Dutch Cancer Society, grants DDHK 2004-3124 and DDHK 2009-4318, the Swedish Cancer Society, the Stockholm Cancer Society, the Gustav V Jubilee foundation, the Bert von Kantzow foundation, the Agency for Science, Technology and Research of Singapore (A∗STAR), the US National Institute of Health (NIH), the Susan G. Komen Breast Cancer Foundation and Märit and Hans Rausings Initiative Against Breast Cancer, the Genome Spain Foundation, the Red Temática de Investigación Coop-erativa en Cáncer and grants from the Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI081583 and PI081120). The ABCFS, NC-BCFR and OFBCR work was supported by the United States National Cancer Institute, National Institutes of Health (NIH) under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Cancer Prevention Institute of California (U01 CA69417) and University of Melbourne (U01 CA69638). Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.
PY - 2012/9
Y1 - 2012/9
N2 - Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
AB - Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
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U2 - 10.1093/hmg/dds159
DO - 10.1093/hmg/dds159
M3 - Article
C2 - 22532573
AN - SCOPUS:84865065666
SN - 0964-6906
VL - 21
SP - 3926
EP - 3939
JO - Human molecular genetics
JF - Human molecular genetics
IS - 17
ER -