Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Bridget Charbonneau; Matthew S Block; William R Bamlet; Robert A Vierkant; Kimberly R Kalli; Zachary Fogarty; David N Rider; Thomas A Sellers; Shelley S Tworoger; Elizabeth Poole; Harvey A Risch; Helga B Salvesen; Lambertus A Kiemeney; Laura Baglietto; Graham G Giles; Gianluca Severi; Britton Trabert; Nicolas Wentzensen; Georgia Chenevix-Trench; Alice S Whittemore; Weiva Sieh; Jenny Chang-Claude; Elisa V Bandera; Irene Orlow; Kathryn Terry; Marc T Goodman; Pamela J Thompson; Linda S Cook; Mary Anne Rossing; Roberta B Ness; Steven A Narod; Jolanta Kupryjanczyk; Karen Lu; Ralf Butzow; Thilo Dörk; Tanja Pejovic; Ian Campbell; Nhu D Le; Clareann H Bunker; Natalia Bogdanova; Ingo B Runnebaum; Diana Eccles; James Paul; Anna H Wu; Simon A Gayther; Estrid Hogdall; Florian Heitz; Claus K Hogdall; Susanne Kruger Kjaer; Allan Jensen; for AOCS/ACS group

doi:10.1158/0008-5472.CAN-13-1051

Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Bridget Charbonneau, Matthew S Block, William R Bamlet, Robert A Vierkant, Kimberly R Kalli, Zachary Fogarty, David N Rider, Thomas A Sellers, Shelley S Tworoger, Elizabeth Poole, Harvey A Risch, Helga B Salvesen, Lambertus A Kiemeney, Laura Baglietto, Graham G Giles, Gianluca Severi, Britton Trabert, Nicolas Wentzensen, Georgia Chenevix-Trench, Alice S WhittemoreWeiva Sieh, Jenny Chang-Claude, Elisa V Bandera, Irene Orlow, Kathryn Terry, Marc T Goodman, Pamela J Thompson, Linda S Cook, Mary Anne Rossing, Roberta B Ness, Steven A Narod, Jolanta Kupryjanczyk, Karen Lu, Ralf Butzow, Thilo Dörk, Tanja Pejovic, Ian Campbell, Nhu D Le, Clareann H Bunker, Natalia Bogdanova, Ingo B Runnebaum, Diana Eccles, James Paul, Anna H Wu, Simon A Gayther, Estrid Hogdall, Florian Heitz, Claus K Hogdall, Susanne Kruger Kjaer, Allan Jensen, for AOCS/ACS group

30 Citations (Scopus)

Abstract

A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1a (IL1A) is both regulated by and able to activate NF-kB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P < 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P < 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 ± 10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P < 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

Original language	English
Journal	Cancer Research
Volume	74
Issue number	3
Pages (from-to)	852-861
Number of pages	10
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.CAN-13-1051
Publication status	Published - 1 Feb 2014

Keywords

Case-Control Studies
Female
Genetic Association Studies
Humans
Interleukin-1alpha
NF-kappa B
Ovarian Neoplasms
Polymorphism, Single Nucleotide
Risk
Signal Transduction
TNF-Related Apoptosis-Inducing Ligand

UN SDGs

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

Access to Document

10.1158/0008-5472.CAN-13-1051

Cite this

Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., ... for AOCS/ACS group (2014). Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10. Cancer Research, 74(3), 852-861. https://doi.org/10.1158/0008-5472.CAN-13-1051

Charbonneau, B, Block, MS, Bamlet, WR, Vierkant, RA, Kalli, KR, Fogarty, Z, Rider, DN, Sellers, TA, Tworoger, SS, Poole, E, Risch, HA, Salvesen, HB, Kiemeney, LA, Baglietto, L, Giles, GG, Severi, G, Trabert, B, Wentzensen, N, Chenevix-Trench, G, Whittemore, AS, Sieh, W, Chang-Claude, J, Bandera, EV, Orlow, I, Terry, K, Goodman, MT, Thompson, PJ, Cook, LS, Rossing, MA, Ness, RB, Narod, SA, Kupryjanczyk, J, Lu, K, Butzow, R, Dörk, T, Pejovic, T, Campbell, I, Le, ND, Bunker, CH, Bogdanova, N, Runnebaum, IB, Eccles, D, Paul, J, Wu, AH, Gayther, SA, Hogdall, E, Heitz, F, Hogdall, CK , Kjaer, SK, Jensen, A & for AOCS/ACS group 2014, 'Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10', Cancer Research, vol. 74, no. 3, pp. 852-861. https://doi.org/10.1158/0008-5472.CAN-13-1051

@article{a537aba8f0e9479abb35f9f1457dba36,

title = "Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10",

abstract = "A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1a (IL1A) is both regulated by and able to activate NF-kB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P < 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P < 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 ± 10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P < 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.",

keywords = "Case-Control Studies, Female, Genetic Association Studies, Humans, Interleukin-1alpha, NF-kappa B, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Risk, Signal Transduction, TNF-Related Apoptosis-Inducing Ligand",

author = "Bridget Charbonneau and Block, {Matthew S} and Bamlet, {William R} and Vierkant, {Robert A} and Kalli, {Kimberly R} and Zachary Fogarty and Rider, {David N} and Sellers, {Thomas A} and Tworoger, {Shelley S} and Elizabeth Poole and Risch, {Harvey A} and Salvesen, {Helga B} and Kiemeney, {Lambertus A} and Laura Baglietto and Giles, {Graham G} and Gianluca Severi and Britton Trabert and Nicolas Wentzensen and Georgia Chenevix-Trench and Whittemore, {Alice S} and Weiva Sieh and Jenny Chang-Claude and Bandera, {Elisa V} and Irene Orlow and Kathryn Terry and Goodman, {Marc T} and Thompson, {Pamela J} and Cook, {Linda S} and Rossing, {Mary Anne} and Ness, {Roberta B} and Narod, {Steven A} and Jolanta Kupryjanczyk and Karen Lu and Ralf Butzow and Thilo D{\"o}rk and Tanja Pejovic and Ian Campbell and Le, {Nhu D} and Bunker, {Clareann H} and Natalia Bogdanova and Runnebaum, {Ingo B} and Diana Eccles and James Paul and Wu, {Anna H} and Gayther, {Simon A} and Estrid Hogdall and Florian Heitz and Hogdall, {Claus K} and Kjaer, {Susanne Kruger} and Allan Jensen and {for AOCS/ACS group}",

year = "2014",

month = feb,

day = "1",

doi = "10.1158/0008-5472.CAN-13-1051",

language = "English",

volume = "74",

pages = "852--861",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

number = "3",

}

TY - JOUR

T1 - Risk of Ovarian Cancer and the NF-κB Pathway

T2 - Genetic Association with IL1A and TNFSF10

AU - Charbonneau, Bridget

AU - Block, Matthew S

AU - Bamlet, William R

AU - Vierkant, Robert A

AU - Kalli, Kimberly R

AU - Fogarty, Zachary

AU - Rider, David N

AU - Sellers, Thomas A

AU - Tworoger, Shelley S

AU - Poole, Elizabeth

AU - Risch, Harvey A

AU - Salvesen, Helga B

AU - Kiemeney, Lambertus A

AU - Baglietto, Laura

AU - Giles, Graham G

AU - Severi, Gianluca

AU - Trabert, Britton

AU - Wentzensen, Nicolas

AU - Chenevix-Trench, Georgia

AU - Whittemore, Alice S

AU - Sieh, Weiva

AU - Chang-Claude, Jenny

AU - Bandera, Elisa V

AU - Orlow, Irene

AU - Terry, Kathryn

AU - Goodman, Marc T

AU - Thompson, Pamela J

AU - Cook, Linda S

AU - Rossing, Mary Anne

AU - Ness, Roberta B

AU - Narod, Steven A

AU - Kupryjanczyk, Jolanta

AU - Lu, Karen

AU - Butzow, Ralf

AU - Dörk, Thilo

AU - Pejovic, Tanja

AU - Campbell, Ian

AU - Le, Nhu D

AU - Bunker, Clareann H

AU - Bogdanova, Natalia

AU - Runnebaum, Ingo B

AU - Eccles, Diana

AU - Paul, James

AU - Wu, Anna H

AU - Gayther, Simon A

AU - Hogdall, Estrid

AU - Heitz, Florian

AU - Hogdall, Claus K

AU - Kjaer, Susanne Kruger

AU - Jensen, Allan

AU - for AOCS/ACS group

PY - 2014/2/1

Y1 - 2014/2/1

N2 - A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1a (IL1A) is both regulated by and able to activate NF-kB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P < 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P < 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 ± 10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P < 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

AB - A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1a (IL1A) is both regulated by and able to activate NF-kB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-kB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P < 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P < 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 ± 10-5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P < 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted.

KW - Case-Control Studies

KW - Female

KW - Genetic Association Studies

KW - Humans

KW - Interleukin-1alpha

KW - NF-kappa B

KW - Ovarian Neoplasms

KW - Polymorphism, Single Nucleotide

KW - Risk

KW - Signal Transduction

KW - TNF-Related Apoptosis-Inducing Ligand

U2 - 10.1158/0008-5472.CAN-13-1051

DO - 10.1158/0008-5472.CAN-13-1051

M3 - Journal article

C2 - 24272484

SN - 0008-5472

VL - 74

SP - 852

EP - 861

JO - Cancer Research

JF - Cancer Research

IS - 3

ER -

Risk of Ovarian Cancer and the NF-κB Pathway: Genetic Association with IL1A and TNFSF10

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this