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

Fagerholm R, Schmidt MK, Khan S, Rafiq S, Tapper W, Aittomäki K, Greco D, Heikkinen T, Muranen TA, Fasching PA, Janni W, Weinshilboum R, Loehberg CR, Hopper JL, Southey MC, Keeman R, Lindblom A, Margolin S, Mannermaa A, Kataja V, Chenevix-Trench G, kConFab InvestigatorsLambrechts D, Wildiers H, Chang-Claude J, Seibold P, Couch FJ, Olson JE, Andrulis IL, Knight JA, García-Closas M, Figueroa J, Hooning MJ, Jager A, Shah M, Perkins BJ, Luben R, Hamann U, Kabisch M, Czene K, Hall P, Easton DF, Pharoah PD, Liu J, Eccles D, Blomqvist C, Nevanlinna H - Oncotarget (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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.

No MeSH data available.


Related in: MedlinePlus

Schematic summary of the putative evidence connecting the rs6500843 SNP to the trans-eQTL SNPs associated with this locusThe eQTL genes marked in bold are associated with the rs6500843 locus at a statistically significant level after conservative Bonferroni correction; the remaining genes listed here are associated with SNP genotype at p < 10-5, and also belong to the Gene Ontology group GO:0007049 (cell cycle) which was most strongly enriched in the DAVID analysis. RBFOX1 and FOXM1 target gene identification is based on previously published data [13, 14].
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Figure 3: Schematic summary of the putative evidence connecting the rs6500843 SNP to the trans-eQTL SNPs associated with this locusThe eQTL genes marked in bold are associated with the rs6500843 locus at a statistically significant level after conservative Bonferroni correction; the remaining genes listed here are associated with SNP genotype at p < 10-5, and also belong to the Gene Ontology group GO:0007049 (cell cycle) which was most strongly enriched in the DAVID analysis. RBFOX1 and FOXM1 target gene identification is based on previously published data [13, 14].

Mentions: Next, we investigated the possible connection between the rs6500843 locus and the trans-eQTL genes. Rs6500843 is located in an intron of RBFOX1, a tissue-specific splicing regulator, for which target genes have been previously published [15]. Given that the genetic neighborhood around rs6500843 contains no other protein coding genes, and little is known about the three RNA coding genes in the region, we operated here under the hypothesis that the SNP is functionally associated with the RBFOX1 gene. As splice variants of gene products may give rise to different signals in microarray experiments, we cross-referenced the published list of RBFOX1 targets against our expanded list of putative trans-eQTL genes (raw p < 10−5 in the eQTL analysis) that also fall within the enriched GO:0007049 (cell cycle) Gene Ontology group (Table 3), and came up with one gene: the transcription factor FOXM1. Genome-wide target genes for FOXM1 have also been previously published [16]; comparison of the statistically significant sites (combined genomic binding and coexpression) with our trans-eQTL list yielded four genes regulated by FOXM1: EXO1, MCM6, UHRF1, and KPNA2. These connections between the genomic locus and the eQTL genes have been schematically summarized in Figure 3.


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

Fagerholm R, Schmidt MK, Khan S, Rafiq S, Tapper W, Aittomäki K, Greco D, Heikkinen T, Muranen TA, Fasching PA, Janni W, Weinshilboum R, Loehberg CR, Hopper JL, Southey MC, Keeman R, Lindblom A, Margolin S, Mannermaa A, Kataja V, Chenevix-Trench G, kConFab InvestigatorsLambrechts D, Wildiers H, Chang-Claude J, Seibold P, Couch FJ, Olson JE, Andrulis IL, Knight JA, García-Closas M, Figueroa J, Hooning MJ, Jager A, Shah M, Perkins BJ, Luben R, Hamann U, Kabisch M, Czene K, Hall P, Easton DF, Pharoah PD, Liu J, Eccles D, Blomqvist C, Nevanlinna H - Oncotarget (2015)

Schematic summary of the putative evidence connecting the rs6500843 SNP to the trans-eQTL SNPs associated with this locusThe eQTL genes marked in bold are associated with the rs6500843 locus at a statistically significant level after conservative Bonferroni correction; the remaining genes listed here are associated with SNP genotype at p < 10-5, and also belong to the Gene Ontology group GO:0007049 (cell cycle) which was most strongly enriched in the DAVID analysis. RBFOX1 and FOXM1 target gene identification is based on previously published data [13, 14].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480688&req=5

Figure 3: Schematic summary of the putative evidence connecting the rs6500843 SNP to the trans-eQTL SNPs associated with this locusThe eQTL genes marked in bold are associated with the rs6500843 locus at a statistically significant level after conservative Bonferroni correction; the remaining genes listed here are associated with SNP genotype at p < 10-5, and also belong to the Gene Ontology group GO:0007049 (cell cycle) which was most strongly enriched in the DAVID analysis. RBFOX1 and FOXM1 target gene identification is based on previously published data [13, 14].
Mentions: Next, we investigated the possible connection between the rs6500843 locus and the trans-eQTL genes. Rs6500843 is located in an intron of RBFOX1, a tissue-specific splicing regulator, for which target genes have been previously published [15]. Given that the genetic neighborhood around rs6500843 contains no other protein coding genes, and little is known about the three RNA coding genes in the region, we operated here under the hypothesis that the SNP is functionally associated with the RBFOX1 gene. As splice variants of gene products may give rise to different signals in microarray experiments, we cross-referenced the published list of RBFOX1 targets against our expanded list of putative trans-eQTL genes (raw p < 10−5 in the eQTL analysis) that also fall within the enriched GO:0007049 (cell cycle) Gene Ontology group (Table 3), and came up with one gene: the transcription factor FOXM1. Genome-wide target genes for FOXM1 have also been previously published [16]; comparison of the statistically significant sites (combined genomic binding and coexpression) with our trans-eQTL list yielded four genes regulated by FOXM1: EXO1, MCM6, UHRF1, and KPNA2. These connections between the genomic locus and the eQTL genes have been schematically summarized in Figure 3.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

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.

No MeSH data available.


Related in: MedlinePlus