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

KConFab investigators

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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<inf>(adjusted)</inf>=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p<inf>(adjusted)</inf>=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(<inf>interaction)</inf>=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.

Original languageEnglish (US)
Pages (from-to)7390-7407
Number of pages18
JournalOncotarget
Volume6
Issue number10
StatePublished - 2015

Fingerprint

Single Nucleotide Polymorphism
Adjuvant Chemotherapy
Breast Neoplasms
Drug Therapy
Survival
Microarray Analysis
Aurora Kinase A
Alleles
Anthracyclines
Cell Cycle Checkpoints
Genes
Genotype
Datasets
Therapeutics

Keywords

  • Breast cancer
  • Cell cycle
  • Chemotherapy
  • SNP
  • Survival

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 10, 2015, p. 7390-7407.

Research output: Contribution to journalArticle

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title = "The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients",
abstract = "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.",
keywords = "Breast cancer, Cell cycle, Chemotherapy, SNP, Survival",
author = "{KConFab investigators} and Rainer Fagerholm and Schmidt, {Marjanka K.} and Sofia Khan and Sajjad Rafiq and William Tapper and Kristiina Aittom{\"a}ki and Dario Greco and Tuomas Heikkinen and Muranen, {Taru A.} and Fasching, {Peter A.} and Wolfgang Janni and Weinshilboum, {Richard M} and Loehberg, {Christian R.} and Hopper, {John L.} and Southey, {Melissa C.} and Renske Keeman and Annika Lindblom and Sara Margolin and Arto Mannermaa and Vesa Kataja and Georgia Chenevix-Trench and Diether Lambrechts and Hans Wildiers and Jenny Chang-Claude and Petra Seibold and Couch, {Fergus J} and Olson, {Janet E} and Andrulis, {Irene L.} and Knight, {Julia A.} and Montserrat Garc{\'i}a-Closas and Jonine Figueroa and Hooning, {Maartje J.} and Agnes Jager and Mitul Shah and Perkins, {Barbara J.} and Robert Luben and Ute Hamann and Maria Kabisch and Kamila Czene and Per Hall and Easton, {Douglas F.} and Pharoah, {Paul D P} and Jianjun Liu and Diana Eccles and Carl Blomqvist and Heli Nevanlinna",
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T1 - The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients

AU - KConFab investigators

AU - Fagerholm, Rainer

AU - Schmidt, Marjanka K.

AU - Khan, Sofia

AU - Rafiq, Sajjad

AU - Tapper, William

AU - Aittomäki, Kristiina

AU - Greco, Dario

AU - Heikkinen, Tuomas

AU - Muranen, Taru A.

AU - Fasching, Peter A.

AU - Janni, Wolfgang

AU - Weinshilboum, Richard M

AU - Loehberg, Christian R.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Keeman, Renske

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Chenevix-Trench, Georgia

AU - Lambrechts, Diether

AU - Wildiers, Hans

AU - Chang-Claude, Jenny

AU - Seibold, Petra

AU - Couch, Fergus J

AU - Olson, Janet E

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - García-Closas, Montserrat

AU - Figueroa, Jonine

AU - Hooning, Maartje J.

AU - Jager, Agnes

AU - Shah, Mitul

AU - Perkins, Barbara J.

AU - Luben, Robert

AU - Hamann, Ute

AU - Kabisch, Maria

AU - Czene, Kamila

AU - Hall, Per

AU - Easton, Douglas F.

AU - Pharoah, Paul D P

AU - Liu, Jianjun

AU - Eccles, Diana

AU - Blomqvist, Carl

AU - Nevanlinna, Heli

PY - 2015

Y1 - 2015

N2 - 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.

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KW - Breast cancer

KW - Cell cycle

KW - Chemotherapy

KW - SNP

KW - Survival

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