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

被引：14

作者：

Fagerholm, Rainer ^{[1
,2
]}

Schmidt, Marjanka K. ^{[3
]}

Khan, Sofia ^{[1
,2
]}

Rafiq, Sajjad ^{[4
]}

Tapper, William ^{[4
]}

Aittomaki, Kristiina ^{[2
,5
]}

Greco, Dario ^{[1
,2
]}

Heikkinen, Tuomas ^{[1
,2
]}

Muranen, Taru A. ^{[1
,2
]}

Fasching, Peter A. ^{[6
,7
]}

Janni, Wolfgang ^{[8
]}

Weinshilboum, Richard ^{[9
]}

Loehberg, Christian R. ^{[10
]}

Hopper, John L. ^{[11
]}

Southey, Melissa C. ^{[12
]}

Keeman, Renske ^{[3
]}

Lindblom, Annika ^{[13
]}

Margolin, Sara ^{[14
]}

Mannermaa, Arto ^{[15
,16
,17
]}

Kataja, Vesa ^{[18
]}

Chenevix-Trench, Georgia ^{[19
]}

Lambrechts, Diether ^{[21
,22
]}

Wildiers, Hans ^{[23
]}

Chang-Claude, Jenny ^{[24
]}

Seibold, Petra ^{[24
]}

Couch, Fergus J. ^{[25
]}

Olson, Janet E. ^{[26
]}

Andrulis, Irene L. ^{[27
,28
]}

Knight, Julia A. ^{[29
,30
]}

Garcia-Closas, Montserrat ^{[31
,32
]}

Figueroa, Jonine ^{[33
]}

Hooning, Maartje J. ^{[34
]}

Jager, Agnes ^{[34
]}

Shah, Mitul ^{[35
]}

Perkins, Barbara J. ^{[35
]}

Luben, Robert ^{[36
]}

Hamann, Ute ^{[37
]}

Kabisch, Maria ^{[37
]}

Czene, Kamila ^{[38
]}

Hall, Per ^{[38
]}

Easton, Douglas F. ^{[39
,40
]}

Pharoah, Paul D. P. ^{[35
,39
]}

Liu, Jianjun ^{[41
]}

Eccles, Diana ^{[4
]}

Blomqvist, Carl ^{[2
,42
]}

Nevanlinna, Heli ^{[1
,2
]}

机构：

[1] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland

[2] Helsinki Univ Hosp, Helsinki, Hus, Finland

[3] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands

[4] Univ Southampton, Southampton Gen Hosp, Fac Med, Southampton, Hants, England

[5] Univ Helsinki, Dept Clin Genet, Helsinki, Finland

[6] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, D-91054 Erlangen, Germany

[7] Univ Calif Los Angeles, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA

[8] Univ Hosp Ulm, Dept Gynecol & Obstet, Ulm, Germany

[9] Mayo Fdn, Mayo Med Sch, Coll Med,Mayo Clin, Div Clin Pharmacol,Dept Mol Pharmacol & Expt Ther, Rochester, MN USA

[10] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Hosp Erlangen, Univ Breast Ctr Franconia,Dept Gynecol & Obstet, D-91054 Erlangen, Germany

[11] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia

[12] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia

[13] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden

[14] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[15] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, Kuopio, Finland

[16] Univ Eastern Finland, Canc Ctr Eastern Finland, Kuopio, Finland

[17] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland

[18] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland

[19] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld, Australia

[20] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[21] Vesalius Res Ctr, Leuven, Belgium

[22] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium

[23] Univ Hosp Leuven, Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium

[24] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[25] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA

[26] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA

[27] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[28] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada

[29] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada

[30] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada

[31] Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England

[32] Inst Canc Res, Div Breast Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England

[33] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA

[34] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands

[35] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB2 1TN, England

[36] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England

[37] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany

[38] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[39] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England

[40] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England

[41] Genome Inst Singapore, Div Human Genet, Singapore, Singapore

[42] Univ Helsinki, Dept Oncol, Helsinki, Hus, Finland

来源：

ONCOTARGET | 2015年 / 6卷 / 10期

基金：

英国医学研究理事会; 芬兰科学院; 美国国家卫生研究院; 加拿大健康研究院;

关键词：

breast cancer; survival; SNP; chemotherapy; cell cycle; ESTROGEN-RECEPTOR-ALPHA; EXPRESSION; PROGNOSIS; REVEALS; GENES; BRCA1; SUSCEPTIBILITY; POLYMORPHISMS; GENOTYPE; OUTCOMES;

D O I：

10.18632/oncotarget.3506

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：7390 / 7407

页数：18

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