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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

Kaplan-Meier curves illustrating cumulative 10-year overall survival among cases of the pooled iCOGS data set categorized by rs6500843 genotypeThe HRs indicate genotype-specific hazard ratios relative to the reference genotype (AA). Censoring marks have been omitted to make the curves clearer. The data set has been subgrouped according to treatment: a) patients treated with any adjuvant chemotherapy, b) patients who did not receive adjuvant chemotherapy.
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Figure 2: Kaplan-Meier curves illustrating cumulative 10-year overall survival among cases of the pooled iCOGS data set categorized by rs6500843 genotypeThe HRs indicate genotype-specific hazard ratios relative to the reference genotype (AA). Censoring marks have been omitted to make the curves clearer. The data set has been subgrouped according to treatment: a) patients treated with any adjuvant chemotherapy, b) patients who did not receive adjuvant chemotherapy.

Mentions: Next, we investigated whether the observed survival effects are specific to the chemotherapy-treated subgroup, and whether these effects occur independently of standard prognostic factors. To this end, we tested for interaction between treatment and the rs6500843 and rs11155012 SNP genotypes in multivariate Cox proportional hazards models adjusted for ER, grade, tumor size, and nodal metastasis. This analysis was only performed in the iCOGS data set, as it contains both treated and non-treated cases in abundant numbers, enabling robust interaction testing. A likelihood-ratio test comparing models with interaction terms with models with only independent covariates indicated an interactive effect between rs6500843 and adjuvant chemotherapy (p(interaction) = 0.0009, N = 9680 [1176 events]; Table 2), consistent with the finding that the SNP was associated with survival in the “any chemotherapy” subset in univariate analysis. See Figure 2 for a visualization of rs6500843-associated survival within the chemotherapy-treated and untreated subgroups in the iCOGS data set. Consistent with the additive model employed in the survival analyses, the genotype-specific hazard ratios for rs6500843 in the chemotherapy-treated group increase in an allele dose dependent manner (HR(AG) = 1.22 (95% C.I. 1.00 - 1.49); HR(GG) = 1.47 (95% C.I. 1.20 - 1.80). In contrast, no heterogeneity between genotypes can be observed in the untreated group. The conclusion of the interaction analysis did not change when radiotherapy, surgery, and adjuvant endocrine therapy were added as additional covariates in the model (p(interaction) = 0.0035, N = 8943 [1110 events]). Despite its association with survival in the anthracycline-treated and any chemotherapy treated subsets, no evidence of interaction was observed for the rs11155012 SNP (Supplementary Table 3), suggesting that its possible association with survival is not entirely treatment-specific.


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)

Kaplan-Meier curves illustrating cumulative 10-year overall survival among cases of the pooled iCOGS data set categorized by rs6500843 genotypeThe HRs indicate genotype-specific hazard ratios relative to the reference genotype (AA). Censoring marks have been omitted to make the curves clearer. The data set has been subgrouped according to treatment: a) patients treated with any adjuvant chemotherapy, b) patients who did not receive adjuvant chemotherapy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Kaplan-Meier curves illustrating cumulative 10-year overall survival among cases of the pooled iCOGS data set categorized by rs6500843 genotypeThe HRs indicate genotype-specific hazard ratios relative to the reference genotype (AA). Censoring marks have been omitted to make the curves clearer. The data set has been subgrouped according to treatment: a) patients treated with any adjuvant chemotherapy, b) patients who did not receive adjuvant chemotherapy.
Mentions: Next, we investigated whether the observed survival effects are specific to the chemotherapy-treated subgroup, and whether these effects occur independently of standard prognostic factors. To this end, we tested for interaction between treatment and the rs6500843 and rs11155012 SNP genotypes in multivariate Cox proportional hazards models adjusted for ER, grade, tumor size, and nodal metastasis. This analysis was only performed in the iCOGS data set, as it contains both treated and non-treated cases in abundant numbers, enabling robust interaction testing. A likelihood-ratio test comparing models with interaction terms with models with only independent covariates indicated an interactive effect between rs6500843 and adjuvant chemotherapy (p(interaction) = 0.0009, N = 9680 [1176 events]; Table 2), consistent with the finding that the SNP was associated with survival in the “any chemotherapy” subset in univariate analysis. See Figure 2 for a visualization of rs6500843-associated survival within the chemotherapy-treated and untreated subgroups in the iCOGS data set. Consistent with the additive model employed in the survival analyses, the genotype-specific hazard ratios for rs6500843 in the chemotherapy-treated group increase in an allele dose dependent manner (HR(AG) = 1.22 (95% C.I. 1.00 - 1.49); HR(GG) = 1.47 (95% C.I. 1.20 - 1.80). In contrast, no heterogeneity between genotypes can be observed in the untreated group. The conclusion of the interaction analysis did not change when radiotherapy, surgery, and adjuvant endocrine therapy were added as additional covariates in the model (p(interaction) = 0.0035, N = 8943 [1110 events]). Despite its association with survival in the anthracycline-treated and any chemotherapy treated subsets, no evidence of interaction was observed for the rs11155012 SNP (Supplementary Table 3), suggesting that its possible association with survival is not entirely treatment-specific.

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