Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Susan J Ramus; Christiana Kartsonaki; Simon A Gayther; Paul D P Pharoah; Olga M Sinilnikova; Jonathan Beesley; Xiaoqing Chen; Lesley McGuffog; Sue Healey; Fergus J Couch; Xianshu Wang; Zachary Fredericksen; Paolo Peterlongo; Siranoush Manoukian; Bernard Peissel; Daniela Zaffaroni; Gaia Roversi; Monica Barile; Alessandra Viel; Anna Allavena; Laura Ottini; Laura Papi; Viviana Gismondi; Fabio Capra; Paolo Radice; Mark H Greene; Phuong L Mai; Irene L Andrulis; Gord Glendon; Hilmi Ozcelik; Mads Thomassen; Anne-Marie Gerdes; Torben A Kruse; Dorthe Cruger; Uffe Birk Jensen; Maria Adelaide Caligo; Håkan Olsson; Ulf Kristoffersson; Annika Lindblom; Brita Arver; Per Karlsson; Marie Stenmark Askmalm; Ake Borg; Susan L Neuhausen; Yuan Chun Ding; Katherine L Nathanson; Susan M Domchek; Anna Jakubowska; Helen Gregory; OCGN; Zosia Miedzybrodzka

doi:10.1093/jnci/djq494

Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Susan J Ramus, Christiana Kartsonaki, Simon A Gayther, Paul D P Pharoah, Olga M Sinilnikova, Jonathan Beesley, Xiaoqing Chen, Lesley McGuffog, Sue Healey, Fergus J Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Gaia Roversi, Monica Barile, Alessandra Viel, Anna AllavenaLaura Ottini, Laura Papi, Viviana Gismondi, Fabio Capra, Paolo Radice, Mark H Greene, Phuong L Mai, Irene L Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A Kruse, Dorthe Cruger, Uffe Birk Jensen, Maria Adelaide Caligo, Håkan Olsson, Ulf Kristoffersson, Annika Lindblom, Brita Arver, Per Karlsson, Marie Stenmark Askmalm, Ake Borg, Susan L Neuhausen, Yuan Chun Ding, Katherine L Nathanson, Susan M Domchek, Anna Jakubowska, Helen Gregory, OCGN, Zosia Miedzybrodzka

Research output: Contribution to journal › Article › peer-review

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Abstract

Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.

Methods We genotyped rs3814113 in 10¿029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.

Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.

Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

Original language	English
Pages (from-to)	105-116
Number of pages	12
Journal	Journal of the National Cancer Institute
Volume	103
Issue number	2
Early online date	17 Dec 2010
DOIs	https://doi.org/10.1093/jnci/djq494
Publication status	Published - 19 Jan 2011

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Ramus, S. J., Kartsonaki, C., Gayther, S. A., Pharoah, P. D. P., Sinilnikova, O. M., Beesley, J., Chen, X., McGuffog, L., Healey, S., Couch, F. J., Wang, X., Fredericksen, Z., Peterlongo, P., Manoukian, S., Peissel, B., Zaffaroni, D., Roversi, G., Barile, M., Viel, A., ... Miedzybrodzka, Z. (2011). Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Journal of the National Cancer Institute, 103(2), 105-116. https://doi.org/10.1093/jnci/djq494

Ramus, SJ, Kartsonaki, C, Gayther, SA, Pharoah, PDP, Sinilnikova, OM, Beesley, J, Chen, X, McGuffog, L, Healey, S, Couch, FJ, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, MH, Mai, PL, Andrulis, IL, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A-M, Kruse, TA, Cruger, D, Jensen, UB, Caligo, MA, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, SL, Ding, YC, Nathanson, KL, Domchek, SM, Jakubowska, A, Gregory, H, OCGN & Miedzybrodzka, Z 2011, 'Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers', Journal of the National Cancer Institute, vol. 103, no. 2, pp. 105-116. https://doi.org/10.1093/jnci/djq494

@article{194000fd4c064b05807a484872594c98,

title = "Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers",

abstract = "Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.Methods We genotyped rs3814113 in 10¿029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.",

author = "Ramus, {Susan J} and Christiana Kartsonaki and Gayther, {Simon A} and Pharoah, {Paul D P} and Sinilnikova, {Olga M} and Jonathan Beesley and Xiaoqing Chen and Lesley McGuffog and Sue Healey and Couch, {Fergus J} and Xianshu Wang and Zachary Fredericksen and Paolo Peterlongo and Siranoush Manoukian and Bernard Peissel and Daniela Zaffaroni and Gaia Roversi and Monica Barile and Alessandra Viel and Anna Allavena and Laura Ottini and Laura Papi and Viviana Gismondi and Fabio Capra and Paolo Radice and Greene, {Mark H} and Mai, {Phuong L} and Andrulis, {Irene L} and Gord Glendon and Hilmi Ozcelik and Mads Thomassen and Anne-Marie Gerdes and Kruse, {Torben A} and Dorthe Cruger and Jensen, {Uffe Birk} and Caligo, {Maria Adelaide} and H{\aa}kan Olsson and Ulf Kristoffersson and Annika Lindblom and Brita Arver and Per Karlsson and {Stenmark Askmalm}, Marie and Ake Borg and Neuhausen, {Susan L} and Ding, {Yuan Chun} and Nathanson, {Katherine L} and Domchek, {Susan M} and Anna Jakubowska and Helen Gregory and OCGN and Zosia Miedzybrodzka",

year = "2011",

month = jan,

day = "19",

doi = "10.1093/jnci/djq494",

language = "English",

volume = "103",

pages = "105--116",

journal = "Journal of the National Cancer Institute",

issn = "1460-2105",

publisher = "Oxford University Press",

number = "2",

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TY - JOUR

T1 - Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

AU - Ramus, Susan J

AU - Kartsonaki, Christiana

AU - Gayther, Simon A

AU - Pharoah, Paul D P

AU - Sinilnikova, Olga M

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Couch, Fergus J

AU - Wang, Xianshu

AU - Fredericksen, Zachary

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Peissel, Bernard

AU - Zaffaroni, Daniela

AU - Roversi, Gaia

AU - Barile, Monica

AU - Viel, Alessandra

AU - Allavena, Anna

AU - Ottini, Laura

AU - Papi, Laura

AU - Gismondi, Viviana

AU - Capra, Fabio

AU - Radice, Paolo

AU - Greene, Mark H

AU - Mai, Phuong L

AU - Andrulis, Irene L

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Thomassen, Mads

AU - Gerdes, Anne-Marie

AU - Kruse, Torben A

AU - Cruger, Dorthe

AU - Jensen, Uffe Birk

AU - Caligo, Maria Adelaide

AU - Olsson, Håkan

AU - Kristoffersson, Ulf

AU - Lindblom, Annika

AU - Arver, Brita

AU - Karlsson, Per

AU - Stenmark Askmalm, Marie

AU - Borg, Ake

AU - Neuhausen, Susan L

AU - Ding, Yuan Chun

AU - Nathanson, Katherine L

AU - Domchek, Susan M

AU - Jakubowska, Anna

AU - Gregory, Helen

AU - OCGN

AU - Miedzybrodzka, Zosia

PY - 2011/1/19

Y1 - 2011/1/19

N2 - Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.Methods We genotyped rs3814113 in 10¿029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

AB - Background Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2.Methods We genotyped rs3814113 in 10¿029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided.Results The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%.Conclusion Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation.

U2 - 10.1093/jnci/djq494

DO - 10.1093/jnci/djq494

M3 - Article

C2 - 21169536

SN - 1460-2105

VL - 103

SP - 105

EP - 116

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 2

ER -

Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

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