The role of genetic breast cancer susceptibility variants as prognostic factors

Peter A. Fasching, Paul D.P. Pharoah, Angela Cox, Heli Nevanlinna, Stig E. Bojesen, Thomas Karn, Annegien Broeks, Flora E. Van Leeuwen, Laura J. Van't Veer, Renate Udo, Alison M. Dunning, Dario Greco, Kristiina Aittomäki, Carl Blomqvist, Mitul Shah, Børge G. Nordestgaard, Henrik Flyger, John L. Hopper, Melissa C. Southey, Carmel ApicellaMontserrat Garcia-Closas, Mark Sherman, Jolanta Lissowska, Caroline Seynaeve, Petra E.A. Huijts, Rob A.E.M. Tollenaar, Argyrios Ziogas, Arif B. Ekici, Claudia Rauh, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Irene L. Andrulis, Hilmi Ozcelik, Anna Marie Mulligan, Gord Glendon, Per Hall, Kamila Czene, Jianjun Liu, Jenny Chang-Claude, Shan Wang-Gohrke, Ursula Eilber, Stefan Nickels, Thilo Dörk, Maria Schiekel, Michael Bremer, Tjoung Won Park-Simon, Graham G. Giles, Gianluca Severi, Laura Baglietto, Maartje J. Hooning, John W.M. Martens, Agnes Jager, Mieke Kriege, Annika Lindblom, Sara Margolin, Fergus J. Couch, Kristen N. Stevens, Janet E. Olson, Matthew Kosel, Simon S. Cross, Sabapathy P. Balasubramanian, Malcolm W.R. Reed, Alexander Miron, Esther M. John, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Georgia Chenevix-Trench, Diether Lambrechts, Anne Sophie Dieudonne, Sigrid Hatse, Erik Van Limbergen, Javier Benitez, Roger L. Milne, M. Pilar Zamora, José Ignacio Arias Pérez, Bernardo Bonanni, Bernard Peissel, Bernard Loris, Paolo Peterlongo, Preetha Rajaraman, Sara J. Schonfeld, Hoda Anton-Culver, Peter Devilee, Matthias W. Beckmann, Dennis J. Slamon, Kelly Anne Phillips, Jonine D. Figueroa, Manjeet K. Humphreys, Douglas F. Easton, Marjanka K. Schmidt

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3926-3939
Number of pages14
JournalHuman molecular genetics
Volume21
Issue number17
DOIs
StatePublished - Sep 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Fasching, P. A., Pharoah, P. D. P., Cox, A., Nevanlinna, H., Bojesen, S. E., Karn, T., Broeks, A., Van Leeuwen, F. E., Van't Veer, L. J., Udo, R., Dunning, A. M., Greco, D., Aittomäki, K., Blomqvist, C., Shah, M., Nordestgaard, B. G., Flyger, H., Hopper, J. L., Southey, M. C., ... Schmidt, M. K. (2012). The role of genetic breast cancer susceptibility variants as prognostic factors. Human molecular genetics, 21(17), 3926-3939. https://doi.org/10.1093/hmg/dds159