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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

Forest plots depicting study-wise hazard ratios for the statistically significant SNPs detected in Stage IIa) Hazard ratios for rs6500843 among cases treated with any adjuvant chemotherapy (additive model); b) Hazard ratios for rs11155012 among anthracycline-treated cases (additive model).
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Figure 1: Forest plots depicting study-wise hazard ratios for the statistically significant SNPs detected in Stage IIa) Hazard ratios for rs6500843 among cases treated with any adjuvant chemotherapy (additive model); b) Hazard ratios for rs11155012 among anthracycline-treated cases (additive model).

Mentions: Finally, we performed a meta-analysis of both the Stage I and Stage II data sets, resulting in very slight improvement in the precision of the per-allele HR estimates for the remaining two SNPs: HR 1.18 (95% C.I. 1.10 – 1.27; p = 6.96 × 10−6) for rs6500843 in the chemotherapy-treated group, and HR 1.23 (95% C.I. 1.11 – 1.37; p = 8.41 × 10−5) for rs11155012 in the anthracycline-treated group. See Figure 1 for forest plots displaying hazard ratios from Stage I and Stage II data sets, as well as from individual participant studies within the iCOGS data set. We detected nominally significant heterogeneity (p = 0.048) among the data sets in the rs6500843 analysis, indicating some disagreement between data sets; the SNP-associated increased hazard was not seen in the SUCCESS-A data set. No heterogeneity was observed in the case of rs11155012 (p = 0.415). Neither rs6500843 nor rs11155012 were associated with tumor histopathological characteristics (Supplementary Table 2), nor were the survival analyses described above adjusted for patient or tumor characteristics except age at diagnosis. More detailed phenotypes were taken into account in the subsequent interaction analyses (see below).


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)

Forest plots depicting study-wise hazard ratios for the statistically significant SNPs detected in Stage IIa) Hazard ratios for rs6500843 among cases treated with any adjuvant chemotherapy (additive model); b) Hazard ratios for rs11155012 among anthracycline-treated cases (additive model).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Forest plots depicting study-wise hazard ratios for the statistically significant SNPs detected in Stage IIa) Hazard ratios for rs6500843 among cases treated with any adjuvant chemotherapy (additive model); b) Hazard ratios for rs11155012 among anthracycline-treated cases (additive model).
Mentions: Finally, we performed a meta-analysis of both the Stage I and Stage II data sets, resulting in very slight improvement in the precision of the per-allele HR estimates for the remaining two SNPs: HR 1.18 (95% C.I. 1.10 – 1.27; p = 6.96 × 10−6) for rs6500843 in the chemotherapy-treated group, and HR 1.23 (95% C.I. 1.11 – 1.37; p = 8.41 × 10−5) for rs11155012 in the anthracycline-treated group. See Figure 1 for forest plots displaying hazard ratios from Stage I and Stage II data sets, as well as from individual participant studies within the iCOGS data set. We detected nominally significant heterogeneity (p = 0.048) among the data sets in the rs6500843 analysis, indicating some disagreement between data sets; the SNP-associated increased hazard was not seen in the SUCCESS-A data set. No heterogeneity was observed in the case of rs11155012 (p = 0.415). Neither rs6500843 nor rs11155012 were associated with tumor histopathological characteristics (Supplementary Table 2), nor were the survival analyses described above adjusted for patient or tumor characteristics except age at diagnosis. More detailed phenotypes were taken into account in the subsequent interaction analyses (see below).

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