Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer

L. Benhaim; W. Zhang; T. Wakatsuki; D. Yang; A. Gerger; P. Bohanes; D. Paez; F. Loupakis; M. J. Labonte; Y. Ning; R. El-Khoueiry; R. Ladner; P. Wilson; H. Zhang; G. Giamas; J. Stebbing; H. J. Lenz

doi:10.1038/tpj.2014.58

Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer

L. Benhaim, W. Zhang, T. Wakatsuki, D. Yang, A. Gerger, P. Bohanes, D. Paez, F. Loupakis, M. J. Labonte, Y. Ning, R. El-Khoueiry, R. Ladner, P. Wilson, H. Zhang, G. Giamas, J. Stebbing, H. J. Lenz

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Résumé

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

langue originale	Anglais
Pages (de - à)	235-240
Nombre de pages	6
journal	Pharmacogenomics Journal
Volume	15
Numéro de publication	3
Les DOIs	https://doi.org/10.1038/tpj.2014.58
état	Publié - 26 juin 2015
Modification externe	Oui

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10.1038/tpj.2014.58

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Benhaim, L., Zhang, W., Wakatsuki, T., Yang, D., Gerger, A., Bohanes, P., Paez, D., Loupakis, F., Labonte, M. J., Ning, Y., El-Khoueiry, R., Ladner, R., Wilson, P., Zhang, H., Giamas, G., Stebbing, J., & Lenz, H. J. (2015). Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer. Pharmacogenomics Journal, 15(3), 235-240. https://doi.org/10.1038/tpj.2014.58

@article{432bf9d918804808bcd877bcc4a26a46,

title = "Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer",

abstract = "In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.",

author = "L. Benhaim and W. Zhang and T. Wakatsuki and D. Yang and A. Gerger and P. Bohanes and D. Paez and F. Loupakis and Labonte, {M. J.} and Y. Ning and R. El-Khoueiry and R. Ladner and P. Wilson and H. Zhang and G. Giamas and J. Stebbing and Lenz, {H. J.}",

year = "2015",

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Benhaim, L, Zhang, W, Wakatsuki, T, Yang, D, Gerger, A, Bohanes, P, Paez, D, Loupakis, F, Labonte, MJ, Ning, Y, El-Khoueiry, R, Ladner, R, Wilson, P, Zhang, H, Giamas, G, Stebbing, J & Lenz, HJ 2015, 'Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer', Pharmacogenomics Journal, VOL. 15, Numéro 3, p. 235-240. https://doi.org/10.1038/tpj.2014.58

TY - JOUR

T1 - Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer

AU - Benhaim, L.

AU - Zhang, W.

AU - Wakatsuki, T.

AU - Yang, D.

AU - Gerger, A.

AU - Bohanes, P.

AU - Paez, D.

AU - Loupakis, F.

AU - Labonte, M. J.

AU - Ning, Y.

AU - El-Khoueiry, R.

AU - Ladner, R.

AU - Wilson, P.

AU - Zhang, H.

AU - Giamas, G.

AU - Stebbing, J.

AU - Lenz, H. J.

PY - 2015/6/26

Y1 - 2015/6/26

N2 - In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

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