Dataset Information

Risk of ovarian cancer and the NF-?B 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-1? (IL1A) is both regulated by and able to activate NF-?B, 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-?B 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.

SUBMITTER: Charbonneau B

PROVIDER: S-EPMC3946482 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.

Charbonneau Bridget B Block Matthew S MS Bamlet William R WR Vierkant Robert A RA Kalli Kimberly R KR Fogarty Zachary Z Rider David N DN Sellers Thomas A TA Tworoger Shelley S SS Poole Elizabeth E Risch Harvey A HA Salvesen Helga B HB Kiemeney Lambertus A LA Baglietto Laura L Giles Graham G GG Severi Gianluca G Trabert Britton B Wentzensen Nicolas N Chenevix-Trench Georgia G Whittemore Alice S AS Sieh Weiva W Chang-Claude Jenny J Bandera Elisa V EV Orlow Irene I Terry Kathryn K Goodman Marc T MT Thompson Pamela J PJ Cook Linda S LS Rossing Mary Anne MA Ness Roberta B RB Narod Steven A SA Kupryjanczyk Jolanta J Lu Karen K Butzow Ralf R Dörk Thilo T Pejovic Tanja T Campbell Ian I Le Nhu D ND Bunker Clareann H CH Bogdanova Natalia N Runnebaum Ingo B IB Eccles Diana D Paul James J Wu Anna H AH Gayther Simon A SA Hogdall Estrid E Heitz Florian F Kaye Stanley B SB Karlan Beth Y BY Anton-Culver Hoda H Gronwald Jacek J Hogdall Claus K CK Lambrechts Diether D Fasching Peter A PA Menon Usha U Schildkraut Joellen J Pearce Celeste Leigh CL Levine Douglas A DA Kjaer Susanne Kruger SK Cramer Daniel D Flanagan James M JM Phelan Catherine M CM Brown Robert R Massuger Leon F A G LF Song Honglin H Doherty Jennifer A JA Krakstad Camilla C Liang Dong D Odunsi Kunle K Berchuck Andrew A Jensen Allan A Lubinski Jan J Nevanlinna Heli H Bean Yukie T YT Lurie Galina G Ziogas Argyrios A Walsh Christine C Despierre Evelyn E Brinton Louise L Hein Alexander A Rudolph Anja A Dansonka-Mieszkowska Agnieszka A Olson Sara H SH Harter Philipp P Tyrer Jonathan J Vitonis Allison F AF Brooks-Wilson Angela A Aben Katja K KK Pike Malcolm C MC Ramus Susan J SJ Wik Elisabeth E Cybulski Cezary C Lin Jie J Sucheston Lara L Edwards Robert R McGuire Valerie V Lester Jenny J du Bois Andreas A Lundvall Lene L Wang-Gohrke Shan S Szafron Lukasz M LM Lambrechts Sandrina S Yang Hannah H Beckmann Matthias W MW Pelttari Liisa M LM Van Altena Anne M AM van den Berg David D Halle Mari K MK Gentry-Maharaj Aleksandra A Schwaab Ira I Chandran Urmila U Menkiszak Janusz J Ekici Arif B AB Wilkens Lynne R LR Leminen Arto A Modugno Francesmary F Friel Grace G Rothstein Joseph H JH Vergote Ignace I Garcia-Closas Montserrat M Hildebrandt Michelle A T MA Sobiczewski Piotr P Kelemen Linda E LE Pharoah Paul D P PD Moysich Kirsten K Knutson Keith L KL Cunningham Julie M JM Fridley Brooke L BL Goode Ellen L EL

Cancer research 20131122 3

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 proinf ...[more]

PMID: 24272484

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Project description:ImportanceBreastfeeding has been associated with a reduced risk of epithelial ovarian cancer in multiple studies, but others showed no association. Whether risk reduction extends beyond that provided by pregnancy alone or differs by histotype is unclear. Furthermore, the observed associations between duration and timing of breastfeeding with ovarian cancer risk have been inconsistent.ObjectiveTo determine the association between breastfeeding (ie, ever/never, duration, timing) and ovarian cancer risk overall and by histotype.Design, setting, and participantsA pooled analysis of parous women with ovarian cancer and controls from 13 case-control studies participating in the Ovarian Cancer Association Consortium was performed. Odds ratios (ORs) and 95% CIs of the overall association were calculated using multivariable logistic regression and polytomous logistic regression for histotype-specific associations. All data were collected from individual sites from November 1989 to December 2009, and analysis took place from September 2017 to July 2019.ExposuresData on breastfeeding history, including duration per child breastfed, age at first and last breastfeeding, and years since last breastfeeding were collected by questionnaire or interview and was harmonized across studies.Main outcomes and measuresDiagnosis of epithelial ovarian cancer.ResultsA total of 9973 women with ovarian cancer (mean [SD] age, 57.4 [11.1] years) and 13 843 controls (mean [SD] age, 56.4 [11.7] years) were included. Breastfeeding was associated with a 24% lower risk of invasive ovarian cancer (odds ratio [OR], 0.76; 95% CI, 0.71-0.80). Independent of parity, ever having breastfed was associated with reduction in risk of all invasive ovarian cancers, particularly high-grade serous and endometrioid cancers. For a single breastfeeding episode, mean breastfeeding duration of 1 to 3 months was associated with 18% lower risk (OR, 0.82; 95% CI, 0.76-0.88), and breastfeeding for 12 or more months was associated with a 34% lower risk (OR, 0.66; 95% CI, 0.58-0.75). More recent breastfeeding was associated with a reduction in risk (OR, 0.56; 95% CI, 0.47-0.66 for <10 years) that persisted for decades (OR, 0.83; 95% CI, 0.77-0.90 for ≥30 years; P for trend = .02).Conclusions and relevanceBreastfeeding is associated with a significant decrease in risk of ovarian cancer overall and for the high-grade serous subtype, the most lethal type of ovarian cancer. The findings suggest that breastfeeding is a potentially modifiable factor that may lower risk of ovarian cancer independent of pregnancy alone.

Project description:Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs).Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n?=?15,748; controls, n?=?18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n?=?14,160; controls, n?=?12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n?=?12,160; controls, n?=?16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma.We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value?=?1.9?×?10-6; top gene RORA, gene P value?=?0.0003), prostate (pathway P value?=?4.1?×?10-6; top gene ARNTL, gene P value?=?0.0002) and lung cancer (pathway P value?=?6.9?×?10-7; top gene RORA, gene P value?=?2.0?×?10-6), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer (ARNTL2, CSNK1E, NR1D2 and PER2) and two for breast cancer (PER1, RORC).Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition.

Dataset Information

Risk of ovarian cancer and the NF-?B pathway: genetic association with IL1A and TNFSF10.

Publications

Risk of ovarian cancer and the NF-κB pathway: genetic association with IL1A and TNFSF10.

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