Genome-wide significant risk associations for mucinous ovarian carcinoma

Linda E Kelemen; Kate Lawrenson; Jonathan Tyrer; Qiyuan Li; Janet M Lee; Ji-Heui Seo; Catherine M Phelan; Jonathan Beesley; Xiaoqing Chen; Tassja J Spindler; Katja K H Aben; Hoda Anton-Culver; Natalia Antonenkova; Australian Cancer Study; Svend Aage Engelholm; Estrid Vilma Solyom Høgdall; Claus Kim Høgdall; Allan Jensen; Susanne Krüger Kjær; Lene Lundvall; Lotte Nedergaard

doi:10.1038/ng.3336

Genome-wide significant risk associations for mucinous ovarian carcinoma

Linda E Kelemen, Kate Lawrenson, Jonathan Tyrer, Qiyuan Li, Janet M Lee, Ji-Heui Seo, Catherine M Phelan, Jonathan Beesley, Xiaoqing Chen, Tassja J Spindler, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Australian Cancer Study, Svend Aage Engelholm, Estrid Vilma Solyom Høgdall, Claus Kim Høgdall, Allan Jensen, Susanne Krüger Kjær, Lene LundvallLotte Nedergaard

Institut for Klinisk Medicin

58 Citationer (Scopus)

Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

Originalsprog	Engelsk
Tidsskrift	Nature Genetics
Vol/bind	47
Udgave nummer	8
Sider (fra-til)	888-97
Antal sider	10
ISSN	1061-4036
DOI	https://doi.org/10.1038/ng.3336
Status	Udgivet - 30 aug. 2015

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Kelemen, L. E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J. M., Seo, J-H., Phelan, C. M., Beesley, J., Chen, X., Spindler, T. J., Aben, K. K. H., Anton-Culver, H., Antonenkova, N., Australian Cancer Study, Engelholm, S. A., Høgdall, E. V. S., Høgdall, C. K., Jensen, A., Kjær, S. K., ... Nedergaard, L. (2015). Genome-wide significant risk associations for mucinous ovarian carcinoma. Nature Genetics, 47(8), 888-97. https://doi.org/10.1038/ng.3336

Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, J-H, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Australian Cancer Study, Engelholm, SA, Høgdall, EVS , Høgdall, CK, Jensen, A, Kjær, SK, Lundvall, L & Nedergaard, L 2015, 'Genome-wide significant risk associations for mucinous ovarian carcinoma', Nature Genetics, bind 47, nr. 8, s. 888-97. https://doi.org/10.1038/ng.3336

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abstract = "Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.",

keywords = "Adenocarcinoma, Mucinous, Base Sequence, Cell Line, Tumor, Cell Nucleus, Chromosomes, Human, Pair 2, Female, Gene Expression Regulation, Neoplastic, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Green Fluorescent Proteins, Homeodomain Proteins, Humans, Microscopy, Fluorescence, Molecular Sequence Data, Neoplasm Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Reverse Transcriptase Polymerase Chain Reaction, Risk Factors",

author = "Kelemen, {Linda E} and Kate Lawrenson and Jonathan Tyrer and Qiyuan Li and Lee, {Janet M} and Ji-Heui Seo and Phelan, {Catherine M} and Jonathan Beesley and Xiaoqing Chen and Spindler, {Tassja J} and Aben, {Katja K H} and Hoda Anton-Culver and Natalia Antonenkova and {Australian Cancer Study} and Engelholm, {Svend Aage} and H{\o}gdall, {Estrid Vilma Solyom} and H{\o}gdall, {Claus Kim} and Allan Jensen and Kj{\ae}r, {Susanne Kr{\"u}ger} and Lene Lundvall and Lotte Nedergaard",

year = "2015",

month = aug,

day = "30",

doi = "10.1038/ng.3336",

language = "English",

volume = "47",

pages = "888--97",

journal = "Nature: New biology",

issn = "1061-4036",

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TY - JOUR

T1 - Genome-wide significant risk associations for mucinous ovarian carcinoma

AU - Kelemen, Linda E

AU - Lawrenson, Kate

AU - Tyrer, Jonathan

AU - Li, Qiyuan

AU - Lee, Janet M

AU - Seo, Ji-Heui

AU - Phelan, Catherine M

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Spindler, Tassja J

AU - Aben, Katja K H

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia

AU - Australian Cancer Study

AU - Engelholm, Svend Aage

AU - Høgdall, Estrid Vilma Solyom

AU - Høgdall, Claus Kim

AU - Jensen, Allan

AU - Kjær, Susanne Krüger

AU - Lundvall, Lene

AU - Nedergaard, Lotte

PY - 2015/8/30

Y1 - 2015/8/30

N2 - Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

AB - Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

KW - Adenocarcinoma, Mucinous

KW - Base Sequence

KW - Cell Line, Tumor

KW - Cell Nucleus

KW - Chromosomes, Human, Pair 2

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Green Fluorescent Proteins

KW - Homeodomain Proteins

KW - Humans

KW - Microscopy, Fluorescence

KW - Molecular Sequence Data

KW - Neoplasm Proteins

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Risk Factors

U2 - 10.1038/ng.3336

DO - 10.1038/ng.3336

M3 - Journal article

C2 - 26075790

SN - 1061-4036

VL - 47

SP - 888

EP - 897

JO - Nature: New biology

JF - Nature: New biology

IS - 8

ER -

Genome-wide significant risk associations for mucinous ovarian carcinoma

Abstract

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