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

Department of Clinical Medicine

58 Citations (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.

Original language	English
Journal	Nature Genetics
Volume	47
Issue number	8
Pages (from-to)	888-97
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3336
Publication status	Published - 30 Aug 2015

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.3336

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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, vol. 47, no. 8, pp. 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.",

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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 Genetics

JF - Nature Genetics

IS - 8

ER -

Genome-wide significant risk associations for mucinous ovarian carcinoma

Abstract

Keywords

UN SDGs

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