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-1α (IL1A) is both regulated by and able to activate NF-κB, 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-κB 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-1α (IL1A) is both regulated by and able to activate NF-κB, 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-κB 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

VL - 74

SP - 852

EP - 861

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 3

ER -