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 Jonson; 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; Bernard Peissel; Siranoush Manoukian; Paolo Radice; Laura Papi; Laura Ottini; Florentia Fostira; Jan C. Oosterwijk; EMBRACE; GEMO Study Collaborators; Breast Cancer Family Registry; HEBON; kConFab Investigators; Australian Canc Study Ovarian Canc; Australian Ovarian Canc Study Grp; Consortium Invest Modifiers BRCA1

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 Jonson, 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, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Laura Papi, Laura Ottini, Florentia Fostira, Jan C. Oosterwijk, EMBRACE, GEMO Study Collaborators, Breast Cancer Family Registry, HEBON, kConFab Investigators, Australian Canc Study Ovarian Canc, Australian Ovarian Canc Study Grp, Consortium Invest Modifiers BRCA1

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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 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Original language	English
Pages (from-to)	164-171
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	2
DOIs	https://doi.org/10.1038/ng.3185
Publication status	Published - Feb-2015

Keywords

BRCA2 MUTATION CARRIERS
GENOME-WIDE ASSOCIATION
ABO BLOOD-GROUP
BREAST-CANCER
GENETIC-VARIATION
COMMON VARIANTS
HUMAN ELG1
RISK
MYOPODIN
METAANALYSIS

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Identification of six new susceptibility loci for invasive epithelial ovarian cancer
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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., ... Consortium Invest Modifiers BRCA1 (2015). Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature Genetics, 47(2), 164-171. https://doi.org/10.1038/ng.3185

@article{f35d4105162a46829739b4f662253170,

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 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.",

keywords = "BRCA2 MUTATION CARRIERS, GENOME-WIDE ASSOCIATION, ABO BLOOD-GROUP, BREAST-CANCER, GENETIC-VARIATION, COMMON VARIANTS, HUMAN ELG1, RISK, MYOPODIN, METAANALYSIS",

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 Jonson 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 Bernard Peissel and Siranoush Manoukian and Paolo Radice and Laura Papi and Laura Ottini and Florentia Fostira and Oosterwijk, {Jan C.} and EMBRACE and {GEMO Study Collaborators} and {Breast Cancer Family Registry} and HEBON and {kConFab Investigators} and {Australian Canc Study Ovarian Canc} and {Australian Ovarian Canc Study Grp} and {Consortium Invest Modifiers BRCA1}",

year = "2015",

month = feb,

doi = "10.1038/ng.3185",

language = "English",

volume = "47",

pages = "164--171",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

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, Jonson, 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, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Oosterwijk, JC, EMBRACE, GEMO Study Collaborators, Breast Cancer Family Registry, HEBON, kConFab Investigators, Australian Canc Study Ovarian Canc, Australian Ovarian Canc Study Grp & Consortium Invest Modifiers BRCA1 2015, 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer', Nature Genetics, vol. 47, no. 2, pp. 164-171. https://doi.org/10.1038/ng.3185

TY - JOUR

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 - Jonson, 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 - Peissel, Bernard

AU - Manoukian, Siranoush

AU - Radice, Paolo

AU - Papi, Laura

AU - Ottini, Laura

AU - Fostira, Florentia

AU - Oosterwijk, Jan C.

AU - EMBRACE

AU - GEMO Study Collaborators

AU - Breast Cancer Family Registry

AU - HEBON

AU - kConFab Investigators

AU - Australian Canc Study Ovarian Canc

AU - Australian Ovarian Canc Study Grp

AU - Consortium Invest Modifiers BRCA1

PY - 2015/2

Y1 - 2015/2

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 x 10(-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 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

KW - BRCA2 MUTATION CARRIERS

KW - GENOME-WIDE ASSOCIATION

KW - ABO BLOOD-GROUP

KW - BREAST-CANCER

KW - GENETIC-VARIATION

KW - COMMON VARIANTS

KW - HUMAN ELG1

KW - RISK

KW - MYOPODIN

KW - METAANALYSIS

U2 - 10.1038/ng.3185

DO - 10.1038/ng.3185

M3 - Article

C2 - 25581431

SN - 1061-4036

VL - 47

SP - 164

EP - 171

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Abstract

Keywords

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