Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Susan J Ramus; Antonis C Antoniou; Karoline B Kuchenbaecker; Penny Soucy; Jonathan Beesley; Xiaoqing Chen; Lesley McGuffog; Olga M Sinilnikova; Sue Healey; Daniel Barrowdale; Andrew Roger Lee; Mads Thomassen; Anne-Marie Gerdes; Torben A Kruse; Uffe Birk Jensen; Anne-Bine Skytte; Maria A Caligo; Annelie Liljegren; Annika Lindblom; Håkan Olsson; Ulf Kristoffersson; Marie Stenmark-Askmalm; Beatrice Melin; Susan M Domchek; Katherine L Nathanson; Timothy R Rebbeck; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska; Katarzyna Durda; Elżbieta Złowocka; Jacek Gronwald; Tomasz Huzarski; Tomasz Byrski; Cezary Cybulski; Aleksandra Toloczko-Grabarek; Ana Osorio; Javier Benitez; Mercedes Duran; Maria-Isabel Tejada; Ute Hamann; Matti Rookus; Flora E van Leeuwen; Cora M Aalfs; Hanne E J Meijers-Heijboer; Christi J van Asperen; K E P van Roozendaal; Nicoline Hoogerbrugge; J Margriet Collée; Mieke Kriege; SWE-BRCA

doi:10.1002/humu.22025

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Susan J Ramus, Antonis C Antoniou, Karoline B Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Olga M Sinilnikova, Sue Healey, Daniel Barrowdale, Andrew Roger Lee, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Uffe Birk Jensen, Anne-Bine Skytte, Maria A Caligo, Annelie Liljegren, Annika Lindblom, Håkan OlssonUlf Kristoffersson, Marie Stenmark-Askmalm, Beatrice Melin, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Aleksandra Toloczko-Grabarek, Ana Osorio, Javier Benitez, Mercedes Duran, Maria-Isabel Tejada, Ute Hamann, Matti Rookus, Flora E van Leeuwen, Cora M Aalfs, Hanne E J Meijers-Heijboer, Christi J van Asperen, K E P van Roozendaal, Nicoline Hoogerbrugge, J Margriet Collée, Mieke Kriege, SWE-BRCA

28 Citations (Scopus)

Abstract

Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

Original language	English
Journal	Human Mutation
Volume	33
Issue number	4
Pages (from-to)	690-702
Number of pages	13
ISSN	1059-7794
DOIs	https://doi.org/10.1002/humu.22025
Publication status	Published - 1 Apr 2012

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Ramus, S. J., Antoniou, A. C., Kuchenbaecker, K. B., Soucy, P., Beesley, J., Chen, X., McGuffog, L., Sinilnikova, O. M., Healey, S., Barrowdale, D., Lee, A. R., Thomassen, M., Gerdes, A-M., Kruse, T. A., Jensen, U. B., Skytte, A-B., Caligo, M. A., Liljegren, A., Lindblom, A., ... SWE-BRCA (2012). Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Human Mutation, 33(4), 690-702. https://doi.org/10.1002/humu.22025

Ramus, SJ, Antoniou, AC, Kuchenbaecker, KB, Soucy, P, Beesley, J, Chen, X, McGuffog, L, Sinilnikova, OM, Healey, S, Barrowdale, D, Lee, AR, Thomassen, M, Gerdes, A-M, Kruse, TA, Jensen, UB, Skytte, A-B, Caligo, MA, Liljegren, A, Lindblom, A, Olsson, H, Kristoffersson, U, Stenmark-Askmalm, M, Melin, B, Domchek, SM, Nathanson, KL, Rebbeck, TR, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Złowocka, E, Gronwald, J, Huzarski, T, Byrski, T, Cybulski, C, Toloczko-Grabarek, A, Osorio, A, Benitez, J, Duran, M, Tejada, M-I, Hamann, U, Rookus, M, van Leeuwen, FE, Aalfs, CM, Meijers-Heijboer, HEJ, van Asperen, CJ, van Roozendaal, KEP, Hoogerbrugge, N, Collée, JM, Kriege, M & SWE-BRCA 2012, 'Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers', Human Mutation, vol. 33, no. 4, pp. 690-702. https://doi.org/10.1002/humu.22025

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title = "Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers",

abstract = "Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.",

author = "Ramus, {Susan J} and Antoniou, {Antonis C} and Kuchenbaecker, {Karoline B} and Penny Soucy and Jonathan Beesley and Xiaoqing Chen and Lesley McGuffog and Sinilnikova, {Olga M} and Sue Healey and Daniel Barrowdale and Lee, {Andrew Roger} and Mads Thomassen and Anne-Marie Gerdes and Kruse, {Torben A} and Jensen, {Uffe Birk} and Anne-Bine Skytte and Caligo, {Maria A} and Annelie Liljegren and Annika Lindblom and H{\aa}kan Olsson and Ulf Kristoffersson and Marie Stenmark-Askmalm and Beatrice Melin and Domchek, {Susan M} and Nathanson, {Katherine L} and Rebbeck, {Timothy R} and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska and Katarzyna Durda and El{\.z}bieta Z{\l}owocka and Jacek Gronwald and Tomasz Huzarski and Tomasz Byrski and Cezary Cybulski and Aleksandra Toloczko-Grabarek and Ana Osorio and Javier Benitez and Mercedes Duran and Maria-Isabel Tejada and Ute Hamann and Matti Rookus and {van Leeuwen}, {Flora E} and Aalfs, {Cora M} and Meijers-Heijboer, {Hanne E J} and {van Asperen}, {Christi J} and {van Roozendaal}, {K E P} and Nicoline Hoogerbrugge and Coll{\'e}e, {J Margriet} and Mieke Kriege and Gerdes, {Anne-Marie Ax{\o}}",

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doi = "10.1002/humu.22025",

language = "English",

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T1 - Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

AU - Ramus, Susan J

AU - Antoniou, Antonis C

AU - Kuchenbaecker, Karoline B

AU - Soucy, Penny

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - McGuffog, Lesley

AU - Sinilnikova, Olga M

AU - Healey, Sue

AU - Barrowdale, Daniel

AU - Lee, Andrew Roger

AU - Thomassen, Mads

AU - Gerdes, Anne-Marie

AU - Kruse, Torben A

AU - Jensen, Uffe Birk

AU - Skytte, Anne-Bine

AU - Caligo, Maria A

AU - Liljegren, Annelie

AU - Lindblom, Annika

AU - Olsson, Håkan

AU - Kristoffersson, Ulf

AU - Stenmark-Askmalm, Marie

AU - Melin, Beatrice

AU - Domchek, Susan M

AU - Nathanson, Katherine L

AU - Rebbeck, Timothy R

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska, Katarzyna

AU - Durda, Katarzyna

AU - Złowocka, Elżbieta

AU - Gronwald, Jacek

AU - Huzarski, Tomasz

AU - Byrski, Tomasz

AU - Cybulski, Cezary

AU - Toloczko-Grabarek, Aleksandra

AU - Osorio, Ana

AU - Benitez, Javier

AU - Duran, Mercedes

AU - Tejada, Maria-Isabel

AU - Hamann, Ute

AU - Rookus, Matti

AU - van Leeuwen, Flora E

AU - Aalfs, Cora M

AU - Meijers-Heijboer, Hanne E J

AU - van Asperen, Christi J

AU - van Roozendaal, K E P

AU - Hoogerbrugge, Nicoline

AU - Collée, J Margriet

AU - Kriege, Mieke

AU - SWE-BRCA

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

AB - Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 × 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 × 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 × 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer.

U2 - 10.1002/humu.22025

DO - 10.1002/humu.22025

M3 - Journal article

C2 - 22253144

SN - 1059-7794

VL - 33

SP - 690

EP - 702

JO - Human Mutation

JF - Human Mutation

IS - 4

ER -

Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

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