Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Karoline B Kuchenbaecker; Susan J Ramus; Jonathan Tyrer; Andrew Lee; Howard C Shen; Jonathan Beesley; Kate Lawrenson; Lesley McGuffog; Sue Healey; Janet M Lee; Tassja J Spindler; Yvonne G Lin; Tanja Pejovic; Yukie Bean; Qiyuan Li; Simon Coetzee; Dennis Hazelett; Alexander Miron; Melissa Southey; Mary Beth Terry; David E Goldgar; Saundra S Buys; Ramunas Janavicius; Cecilia M Dorfling; Elizabeth J van Rensburg; Susan L Neuhausen; Yuan Chun Ding; Thomas V O Hansen; Lars Jønson; Anne-Marie Gerdes; Bent Ejlertsen; Daniel Barrowdale; Joe Dennis; Javier Benitez; Ana Osorio; Maria Jose Garcia; Ian Komenaka; Jeffrey N Weitzel; Pamela Ganschow; Paolo Peterlongo; Loris Bernard; Alessandra Viel; Bernardo Bonanni; Allan Jensen; Susanne Kruger Kjaer; Estrid Hogdall; Claus Hogdall; Lene Lundvall; Lotte Nedergaard; Yu-Tang Gao; EMBRACE

doi:10.1038/ng.3185

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Karoline B Kuchenbaecker, Susan J Ramus, Jonathan Tyrer, Andrew Lee, Howard C Shen, Jonathan Beesley, Kate Lawrenson, Lesley McGuffog, Sue Healey, Janet M Lee, Tassja J Spindler, Yvonne G Lin, Tanja Pejovic, Yukie Bean, Qiyuan Li, Simon Coetzee, Dennis Hazelett, Alexander Miron, Melissa Southey, Mary Beth TerryDavid E Goldgar, Saundra S Buys, Ramunas Janavicius, Cecilia M Dorfling, Elizabeth J van Rensburg, Susan L Neuhausen, Yuan Chun Ding, Thomas V O Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Daniel Barrowdale, Joe Dennis, Javier Benitez, Ana Osorio, Maria Jose Garcia, Ian Komenaka, Jeffrey N Weitzel, Pamela Ganschow, Paolo Peterlongo, Loris Bernard, Alessandra Viel, Bernardo Bonanni, Allan Jensen, Susanne Kruger Kjaer, Estrid Hogdall, Claus Hogdall, Lene Lundvall, Lotte Nedergaard, Yu-Tang Gao, EMBRACE

154 Citationer (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10−8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	2
Sider (fra-til)	164-71, 3 unpag. p.
Antal sider	11
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3185
Status	Udgivet - 1 jan. 2015

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Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J. M., Spindler, T. J., Lin, Y. G., Pejovic, T., Bean, Y., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., ... EMBRACE (2015). Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature Genetics, 47(2), 164-71, 3 unpag. p. https://doi.org/10.1038/ng.3185

Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jønson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Jensen, A, Kjaer, SK , Hogdall, E , Hogdall, C, Lundvall, L, Nedergaard, L, Gao, Y-T & EMBRACE 2015, 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer', Nature Genetics, bind 47, nr. 2, s. 164-71, 3 unpag. p. https://doi.org/10.1038/ng.3185

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title = "Identification of six new susceptibility loci for invasive epithelial ovarian cancer",

abstract = "Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10 {\^a}+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.",

keywords = "Adolescent, Adult, Alleles, BRCA1 Protein, BRCA2 Protein, Female, Genes, Reporter, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Heterozygote, Humans, Mutation, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Young Adult",

author = "Kuchenbaecker, {Karoline B} and Ramus, {Susan J} and Jonathan Tyrer and Andrew Lee and Shen, {Howard C} and Jonathan Beesley and Kate Lawrenson and Lesley McGuffog and Sue Healey and Lee, {Janet M} and Spindler, {Tassja J} and Lin, {Yvonne G} and Tanja Pejovic and Yukie Bean and Qiyuan Li and Simon Coetzee and Dennis Hazelett and Alexander Miron and Melissa Southey and Terry, {Mary Beth} and Goldgar, {David E} and Buys, {Saundra S} and Ramunas Janavicius and Dorfling, {Cecilia M} and {van Rensburg}, {Elizabeth J} and Neuhausen, {Susan L} and Ding, {Yuan Chun} and Hansen, {Thomas V O} and Lars J{\o}nson and Anne-Marie Gerdes and Bent Ejlertsen and Daniel Barrowdale and Joe Dennis and Javier Benitez and Ana Osorio and Garcia, {Maria Jose} and Ian Komenaka and Weitzel, {Jeffrey N} and Pamela Ganschow and Paolo Peterlongo and Loris Bernard and Alessandra Viel and Bernardo Bonanni and Allan Jensen and Kjaer, {Susanne Kruger} and Estrid Hogdall and Claus Hogdall and Lene Lundvall and Lotte Nedergaard and Yu-Tang Gao and EMBRACE",

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T1 - Identification of six new susceptibility loci for invasive epithelial ovarian cancer

AU - Kuchenbaecker, Karoline B

AU - Ramus, Susan J

AU - Tyrer, Jonathan

AU - Lee, Andrew

AU - Shen, Howard C

AU - Beesley, Jonathan

AU - Lawrenson, Kate

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Lee, Janet M

AU - Spindler, Tassja J

AU - Lin, Yvonne G

AU - Pejovic, Tanja

AU - Bean, Yukie

AU - Li, Qiyuan

AU - Coetzee, Simon

AU - Hazelett, Dennis

AU - Miron, Alexander

AU - Southey, Melissa

AU - Terry, Mary Beth

AU - Goldgar, David E

AU - Buys, Saundra S

AU - Janavicius, Ramunas

AU - Dorfling, Cecilia M

AU - van Rensburg, Elizabeth J

AU - Neuhausen, Susan L

AU - Ding, Yuan Chun

AU - Hansen, Thomas V O

AU - Jønson, Lars

AU - Gerdes, Anne-Marie

AU - Ejlertsen, Bent

AU - Barrowdale, Daniel

AU - Dennis, Joe

AU - Benitez, Javier

AU - Osorio, Ana

AU - Garcia, Maria Jose

AU - Komenaka, Ian

AU - Weitzel, Jeffrey N

AU - Ganschow, Pamela

AU - Peterlongo, Paolo

AU - Bernard, Loris

AU - Viel, Alessandra

AU - Bonanni, Bernardo

AU - Jensen, Allan

AU - Kjaer, Susanne Kruger

AU - Hogdall, Estrid

AU - Hogdall, Claus

AU - Lundvall, Lene

AU - Nedergaard, Lotte

AU - Gao, Yu-Tang

AU - EMBRACE

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

AB - Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

KW - Adolescent

KW - Adult

KW - Alleles

KW - BRCA1 Protein

KW - BRCA2 Protein

KW - Female

KW - Genes, Reporter

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - Heterozygote

KW - Humans

KW - Mutation

KW - Neoplasms, Glandular and Epithelial

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Risk

KW - Young Adult

U2 - 10.1038/ng.3185

DO - 10.1038/ng.3185

M3 - Letter

C2 - 25581431

SN - 1061-4036

VL - 47

SP - 164-71, 3 unpag. p.

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

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