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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 and Lee, Janet M, et al. (2015) In Nature Genetics 47(2). p.71-164
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),... (More)

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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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, Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
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Nature Genetics
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47
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2
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8 pages
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Nature Publishing Group
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  • pmid:25581431
  • wos:000348694700012
  • scopus:84929171835
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1546-1718
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10.1038/ng.3185
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English
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64aad5fe-991c-4959-a907-af91c0c9011e (old id 5040500)
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http://www.ncbi.nlm.nih.gov/pubmed/25581431?dopt=Abstract
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2015-02-02 21:41:01
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2018-06-17 03:00:51
@article{64aad5fe-991c-4959-a907-af91c0c9011e,
  abstract     = {<p>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 &lt; 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.</p>},
  author       = {Kuchenbaecker, Karoline B and Ramus, Susan J and Tyrer, Jonathan and Lee, Andrew and Shen, Howard C and Beesley, Jonathan and Lawrenson, Kate and McGuffog, Lesley and Healey, Sue and Lee, Janet M and Spindler, Tassja J and Lin, Yvonne G and Pejovic, Tanja and Bean, Yukie and Li, Qiyuan and Coetzee, Simon and Hazelett, Dennis and Miron, Alexander and Southey, Melissa and Terry, Mary Beth and Goldgar, David E and Buys, Saundra S and Janavicius, Ramunas and Dorfling, Cecilia M and van Rensburg, Elizabeth J and Neuhausen, Susan L and Ding, Yuan Chun and Hansen, Thomas V O and Jønson, Lars and Gerdes, Anne-Marie and Ejlertsen, Bent and Barrowdale, Daniel and Dennis, Joe and Benitez, Javier and Osorio, Ana and Garcia, Maria Jose and Komenaka, Ian and Weitzel, Jeffrey N and Ganschow, Pamela and Peterlongo, Paolo and Bernard, Loris and Viel, Alessandra and Bonanni, Bernardo and Peissel, Bernard and Manoukian, Siranoush and Radice, Paolo and Papi, Laura and Ottini, Laura and Soller, Maria and Stenmark-Askmalm, Marie and , },
  issn         = {1546-1718},
  keyword      = {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,Journal Article,Meta-Analysis,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {2},
  pages        = {71--164},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Identification of six new susceptibility loci for invasive epithelial ovarian cancer},
  url          = {http://dx.doi.org/10.1038/ng.3185},
  volume       = {47},
  year         = {2015},
}