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 & 31 others 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, Bernard Peissel, Siranoush Manoukian, Paolo Radice, Laura Papi, Laura Ottini, Wei Zheng, EMBRACE, Zofia Helena Miedzybrodzka

Research output: Contribution to journalLetter

126 Citations (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.

Original languageEnglish
Pages (from-to)164-171
Number of pages8
JournalNature Genetics
Volume47
Issue number2
Early online date12 Jan 2015
DOIs
Publication statusPublished - Feb 2015

Fingerprint

Mutation
Genome-Wide Association Study
Ovarian Neoplasms
Meta-Analysis
Ovarian epithelial cancer
Alleles
Genome
Genes

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

Cite this

Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., ... Miedzybrodzka, Z. H. (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

Identification of six new susceptibility loci for invasive epithelial ovarian cancer. / Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; Spindler, Tassja J; Lin, Yvonne G; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Zheng, Wei; EMBRACE ; Miedzybrodzka, Zofia Helena.

In: Nature Genetics, Vol. 47, No. 2, 02.2015, p. 164-171.

Research output: Contribution to journalLetter

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, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Zheng, W, EMBRACE & Miedzybrodzka, ZH 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
Kuchenbaecker KB, Ramus SJ, Tyrer J, Lee A, Shen HC, Beesley J et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature Genetics. 2015 Feb;47(2):164-171. https://doi.org/10.1038/ng.3185
Kuchenbaecker, Karoline B ; Ramus, Susan J ; Tyrer, Jonathan ; Lee, Andrew ; Shen, Howard C ; Beesley, Jonathan ; Lawrenson, Kate ; McGuffog, Lesley ; Healey, Sue ; Lee, Janet M ; Spindler, Tassja J ; Lin, Yvonne G ; Pejovic, Tanja ; Bean, Yukie ; Li, Qiyuan ; Coetzee, Simon ; Hazelett, Dennis ; Miron, Alexander ; Southey, Melissa ; Terry, Mary Beth ; Goldgar, David E ; Buys, Saundra S ; Janavicius, Ramunas ; Dorfling, Cecilia M ; van Rensburg, Elizabeth J ; Neuhausen, Susan L ; Ding, Yuan Chun ; Hansen, Thomas V O ; Jønson, Lars ; Gerdes, Anne-Marie ; Ejlertsen, Bent ; Barrowdale, Daniel ; Dennis, Joe ; Benitez, Javier ; Osorio, Ana ; Garcia, Maria Jose ; Komenaka, Ian ; Weitzel, Jeffrey N ; Ganschow, Pamela ; Peterlongo, Paolo ; Bernard, Loris ; Viel, Alessandra ; Bonanni, Bernardo ; Peissel, Bernard ; Manoukian, Siranoush ; Radice, Paolo ; Papi, Laura ; Ottini, Laura ; Zheng, Wei ; EMBRACE ; Miedzybrodzka, Zofia Helena. / Identification of six new susceptibility loci for invasive epithelial ovarian cancer. In: Nature Genetics. 2015 ; Vol. 47, No. 2. pp. 164-171.
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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 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.",
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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(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

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KW - Alleles

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KW - BRCA2 Protein

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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

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