The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

• Published in: Oncotarget 2015-04, Vol.6 (10), p.7390-7407
• Main Authors: Fagerholm, Rainer, Schmidt, Marjanka K, Khan, Sofia, Rafiq, Sajjad, Tapper, William, Aittomäki, Kristiina, Greco, Dario, Heikkinen, Tuomas, Muranen, Taru A, Fasching, Peter A, Janni, Wolfgang, Weinshilboum, Richard, Loehberg, Christian R, Hopper, John L, Southey, Melissa C, Keeman, Renske, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Chenevix-Trench, Georgia, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Seibold, Petra, Couch, Fergus J, Olson, Janet E, Andrulis, Irene L, Knight, Julia A, García-Closas, Montserrat, Figueroa, Jonine, Hooning, Maartje J, Jager, Agnes, Shah, Mitul, Perkins, Barbara J, Luben, Robert, Hamann, Ute, Kabisch, Maria, Czene, Kamila, Hall, Per, Easton, Douglas F, Pharoah, Paul D P, Liu, Jianjun, Eccles, Diana, Blomqvist, Carl, Nevanlinna, Heli
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anthracyclines - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - surgery; Chemotherapy, Adjuvant; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Female; Gemcitabine; Genome-Wide Association Study; Humans; Middle Aged; Multivariate Analysis; Polymorphism, Single Nucleotide; Priority Research Paper; Prognosis; Quantitative Trait Loci; Survival Analysis; Taxoids - administration & dosage; Young Adult
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3506

We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway.