Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival

E.M. Azzato; J. Tyrer; P.A. Fasching; M.W. Beckmann; A.B. Ekici; R. Schulz-Wendtland; S.E. Bojesen; B.G. Nordestgaard; H. Flyger; R.L. Milne; J.I. Arias; P. Menendez; J. Benitez; J. Chang-Claude; R. Hein; S. Wang-Gohrke; H. Nevanlinna; T. Heikkinen; K. Aittomaki; C. Blomqvist; S. Margolin; A. Mannermaa; V.M. Kosma; V. Kataja; J. Beesley; X.Q. Chen; G. Chenevix-Trench; F.J. Couch; J.E. Olson; Z.S. Fredericksen; X.S. Wang; Giles Gaubert; G. Severi; L. Baglietto; M.C. Southey; P. Devilee; R.A.E.M. Tollenaar; C. Seynaeve; M. Garcia-Closas; J. Lissowska; M.E. Sherman; K.L. Bolton; Katrine Blædel Pinholt Hall; K. Czene; A. Cox; I.W. Brock; George Arthur Elliott; Brandon Reed Travis; D. Greenberg; H. Anton-Culver; A. Ziogas; M. Humphreys; D.F. Easton; N.E. Caporaso; P.D.P. Pharoah

Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival

E.M. Azzato, J. Tyrer, P.A. Fasching, M.W. Beckmann, A.B. Ekici, R. Schulz-Wendtland, S.E. Bojesen, B.G. Nordestgaard, H. Flyger, R.L. Milne, J.I. Arias, P. Menendez, J. Benitez, J. Chang-Claude, R. Hein, S. Wang-Gohrke, H. Nevanlinna, T. Heikkinen, K. Aittomaki, C. BlomqvistS. Margolin, A. Mannermaa, V.M. Kosma, V. Kataja, J. Beesley, X.Q. Chen, G. Chenevix-Trench, F.J. Couch, J.E. Olson, Z.S. Fredericksen, X.S. Wang, Giles Gaubert, G. Severi, L. Baglietto, M.C. Southey, P. Devilee, R.A.E.M. Tollenaar, C. Seynaeve, M. Garcia-Closas, J. Lissowska, M.E. Sherman, K.L. Bolton, Katrine Blædel Pinholt Hall, K. Czene, A. Cox, I.W. Brock, George Arthur Elliott, Brandon Reed Travis, D. Greenberg, H. Anton-Culver, A. Ziogas, M. Humphreys, D.F. Easton, N.E. Caporaso, P.D.P. Pharoah

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Abstract

Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10^-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10^-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Translated title of the contribution	Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival
Original language	English
Journal	National Cancer Institute. Journal (Print)
Volume	102
Issue number	9
Pages (from-to)	650-662
Number of pages	13
ISSN	0027-8874
Publication status	Published - May 2010

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Azzato, E. M., Tyrer, J., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Schulz-Wendtland, R., Bojesen, S. E., Nordestgaard, B. G., Flyger, H., Milne, R. L., Arias, J. I., Menendez, P., Benitez, J., Chang-Claude, J., Hein, R., Wang-Gohrke, S., Nevanlinna, H., Heikkinen, T., Aittomaki, K., ... Pharoah, P. D. P. (2010). Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival. National Cancer Institute. Journal (Print), 102(9), 650-662.

Azzato, EM, Tyrer, J, Fasching, PA, Beckmann, MW, Ekici, AB, Schulz-Wendtland, R, Bojesen, SE , Nordestgaard, BG, Flyger, H, Milne, RL, Arias, JI, Menendez, P, Benitez, J, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Margolin, S, Mannermaa, A, Kosma, VM, Kataja, V, Beesley, J, Chen, XQ, Chenevix-Trench, G, Couch, FJ, Olson, JE, Fredericksen, ZS, Wang, XS, Gaubert, G, Severi, G, Baglietto, L, Southey, MC, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Lissowska, J, Sherman, ME, Bolton, KL, Hall, KBP, Czene, K, Cox, A, Brock, IW, Elliott, GA, Travis, BR, Greenberg, D, Anton-Culver, H, Ziogas, A, Humphreys, M, Easton, DF, Caporaso, NE & Pharoah, PDP 2010, 'Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival', National Cancer Institute. Journal (Print), vol. 102, no. 9, pp. 650-662.

@article{736aad37f1944d94a659174879eecc02,

title = "Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival",

abstract = "Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.",

author = "E.M. Azzato and J. Tyrer and P.A. Fasching and M.W. Beckmann and A.B. Ekici and R. Schulz-Wendtland and S.E. Bojesen and B.G. Nordestgaard and H. Flyger and R.L. Milne and J.I. Arias and P. Menendez and J. Benitez and J. Chang-Claude and R. Hein and S. Wang-Gohrke and H. Nevanlinna and T. Heikkinen and K. Aittomaki and C. Blomqvist and S. Margolin and A. Mannermaa and V.M. Kosma and V. Kataja and J. Beesley and X.Q. Chen and G. Chenevix-Trench and F.J. Couch and J.E. Olson and Z.S. Fredericksen and X.S. Wang and Giles Gaubert and G. Severi and L. Baglietto and M.C. Southey and P. Devilee and R.A.E.M. Tollenaar and C. Seynaeve and M. Garcia-Closas and J. Lissowska and M.E. Sherman and K.L. Bolton and Hall, {Katrine Bl{\ae}del Pinholt} and K. Czene and A. Cox and I.W. Brock and Elliott, {George Arthur} and Travis, {Brandon Reed} and D. Greenberg and H. Anton-Culver and A. Ziogas and M. Humphreys and D.F. Easton and N.E. Caporaso and P.D.P. Pharoah",

year = "2010",

month = may,

language = "English",

volume = "102",

pages = "650--662",

journal = "National Cancer Institute. Journal (Print)",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "9",

}

TY - JOUR

T1 - Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival

AU - Azzato, E.M.

AU - Tyrer, J.

AU - Fasching, P.A.

AU - Beckmann, M.W.

AU - Ekici, A.B.

AU - Schulz-Wendtland, R.

AU - Bojesen, S.E.

AU - Nordestgaard, B.G.

AU - Flyger, H.

AU - Milne, R.L.

AU - Arias, J.I.

AU - Menendez, P.

AU - Benitez, J.

AU - Chang-Claude, J.

AU - Hein, R.

AU - Wang-Gohrke, S.

AU - Nevanlinna, H.

AU - Heikkinen, T.

AU - Aittomaki, K.

AU - Blomqvist, C.

AU - Margolin, S.

AU - Mannermaa, A.

AU - Kosma, V.M.

AU - Kataja, V.

AU - Beesley, J.

AU - Chen, X.Q.

AU - Chenevix-Trench, G.

AU - Couch, F.J.

AU - Olson, J.E.

AU - Fredericksen, Z.S.

AU - Wang, X.S.

AU - Gaubert, Giles

AU - Severi, G.

AU - Baglietto, L.

AU - Southey, M.C.

AU - Devilee, P.

AU - Tollenaar, R.A.E.M.

AU - Seynaeve, C.

AU - Garcia-Closas, M.

AU - Lissowska, J.

AU - Sherman, M.E.

AU - Bolton, K.L.

AU - Hall, Katrine Blædel Pinholt

AU - Czene, K.

AU - Cox, A.

AU - Brock, I.W.

AU - Elliott, George Arthur

AU - Travis, Brandon Reed

AU - Greenberg, D.

AU - Anton-Culver, H.

AU - Ziogas, A.

AU - Humphreys, M.

AU - Easton, D.F.

AU - Caporaso, N.E.

AU - Pharoah, P.D.P.

PY - 2010/5

Y1 - 2010/5

N2 - Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

AB - Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

M3 - Journal article

SN - 0027-8874

VL - 102

SP - 650

EP - 662

JO - National Cancer Institute. Journal (Print)

JF - National Cancer Institute. Journal (Print)

IS - 9

ER -

Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival

Abstract

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