Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Madalene A Earp; Linda E Kelemen; Anthony M Magliocco; Kenneth D Swenerton; Georgia Chenevix-Trench; Yi Lu; Alexander Hein; Arif B Ekici; Matthias W Beckmann; Peter A Fasching; Diether Lambrechts; Evelyn Despierre; Ignace Vergote; Sandrina Lambrechts; Jennifer A Doherty; Mary Anne Rossing; Jenny Chang-Claude; Anja Rudolph; Grace Friel; Kirsten B Moysich; Kunle Odunsi; Lara Sucheston-Campbell; Galina Lurie; Marc T Goodman; Michael E Carney; Pamela J Thompson; Ingo B Runnebaum; Matthias Dürst; Peter Hillemanns; Thilo Dörk; Natalia Antonenkova; Natalia Bogdanova; Arto Leminen; Heli Nevanlinna; Liisa M Pelttari; Ralf Butzow; Clareann H Bunker; Francesmary Modugno; Robert P Edwards; Roberta B Ness; Andreas du Bois; Florian Heitz; Ira Schwaab; Philipp Harter; Beth Y Karlan; Christine Walsh; Jenny Lester; Allan Jensen; Susanne K Kjær; Claus K Høgdall; Australian Cancer Study

doi:10.1007/s00439-013-1383-3

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Madalene A Earp, Linda E Kelemen, Anthony M Magliocco, Kenneth D Swenerton, Georgia Chenevix-Trench, Yi Lu, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Peter A Fasching, Diether Lambrechts, Evelyn Despierre, Ignace Vergote, Sandrina Lambrechts, Jennifer A Doherty, Mary Anne Rossing, Jenny Chang-Claude, Anja Rudolph, Grace Friel, Kirsten B MoysichKunle Odunsi, Lara Sucheston-Campbell, Galina Lurie, Marc T Goodman, Michael E Carney, Pamela J Thompson, Ingo B Runnebaum, Matthias Dürst, Peter Hillemanns, Thilo Dörk, Natalia Antonenkova, Natalia Bogdanova, Arto Leminen, Heli Nevanlinna, Liisa M Pelttari, Ralf Butzow, Clareann H Bunker, Francesmary Modugno, Robert P Edwards, Roberta B Ness, Andreas du Bois, Florian Heitz, Ira Schwaab, Philipp Harter, Beth Y Karlan, Christine Walsh, Jenny Lester, Allan Jensen, Susanne K Kjær, Claus K Høgdall, Australian Cancer Study

18 Citations (Scopus)

Abstract

Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

Original language	English
Journal	Human Genetics
Volume	133
Issue number	5
Pages (from-to)	481-497
Number of pages	17
ISSN	0340-6717
DOIs	https://doi.org/10.1007/s00439-013-1383-3
Publication status	Published - May 2014

Keywords

Alleles
DNA
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Neoplasms, Glandular and Epithelial
Ovarian Neoplasms
Polymorphism, Single Nucleotide
Quality Control

UN SDGs

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

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10.1007/s00439-013-1383-3

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Earp, M. A., Kelemen, L. E., Magliocco, A. M., Swenerton, K. D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Friel, G., ... Australian Cancer Study (2014). Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Human Genetics, 133(5), 481-497. https://doi.org/10.1007/s00439-013-1383-3

Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Dürst, M, Hillemanns, P, Dörk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, Modugno, F, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjær, SK , Høgdall, CK & Australian Cancer Study 2014, 'Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA', Human Genetics, vol. 133, no. 5, pp. 481-497. https://doi.org/10.1007/s00439-013-1383-3

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title = "Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA",

abstract = "Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.",

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year = "2014",

month = may,

doi = "10.1007/s00439-013-1383-3",

language = "English",

volume = "133",

pages = "481--497",

journal = "Human Genetics",

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T1 - Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

AU - Earp, Madalene A

AU - Kelemen, Linda E

AU - Magliocco, Anthony M

AU - Swenerton, Kenneth D

AU - Chenevix-Trench, Georgia

AU - Lu, Yi

AU - Hein, Alexander

AU - Ekici, Arif B

AU - Beckmann, Matthias W

AU - Fasching, Peter A

AU - Lambrechts, Diether

AU - Despierre, Evelyn

AU - Vergote, Ignace

AU - Lambrechts, Sandrina

AU - Doherty, Jennifer A

AU - Rossing, Mary Anne

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Friel, Grace

AU - Moysich, Kirsten B

AU - Odunsi, Kunle

AU - Sucheston-Campbell, Lara

AU - Lurie, Galina

AU - Goodman, Marc T

AU - Carney, Michael E

AU - Thompson, Pamela J

AU - Runnebaum, Ingo B

AU - Dürst, Matthias

AU - Hillemanns, Peter

AU - Dörk, Thilo

AU - Antonenkova, Natalia

AU - Bogdanova, Natalia

AU - Leminen, Arto

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M

AU - Butzow, Ralf

AU - Bunker, Clareann H

AU - Modugno, Francesmary

AU - Edwards, Robert P

AU - Ness, Roberta B

AU - du Bois, Andreas

AU - Heitz, Florian

AU - Schwaab, Ira

AU - Harter, Philipp

AU - Karlan, Beth Y

AU - Walsh, Christine

AU - Lester, Jenny

AU - Jensen, Allan

AU - Kjær, Susanne K

AU - Høgdall, Claus K

AU - Australian Cancer Study

PY - 2014/5

Y1 - 2014/5

N2 - Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

AB - Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

KW - Alleles

KW - DNA

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Neoplasms, Glandular and Epithelial

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Quality Control

U2 - 10.1007/s00439-013-1383-3

DO - 10.1007/s00439-013-1383-3

M3 - Journal article

C2 - 24190013

SN - 0340-6717

VL - 133

SP - 481

EP - 497

JO - Human Genetics

JF - Human Genetics

IS - 5

ER -

Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Abstract

Keywords

UN SDGs

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