Dataset Information

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

ABSTRACT: Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

SUBMITTER: Block MS

PROVIDER: S-EPMC4082406 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Block Matthew S MS Charbonneau Bridget B Vierkant Robert A RA Fogarty Zachary Z Bamlet William R WR Pharoah Paul D P PD Rossing Mary Anne MA Cramer Daniel D Pearce Celeste Leigh CL Schildkraut Joellen J Menon Usha U Kjaer Susanne K SK Levine Douglas A DA Gronwald Jacek J Culver Hoda Anton HA Whittemore Alice S AS Karlan Beth Y BY Lambrechts Diether D Wentzensen Nicolas N Kupryjanczyk Jolanta J Chang-Claude Jenny J Bandera Elisa V EV Hogdall Estrid E Heitz Florian F Kaye Stanley B SB Fasching Peter A PA Campbell Ian I Goodman Marc T MT Pejovic Tanja T Bean Yukie T YT Hays Laura E LE Lurie Galina G Eccles Diana D Hein Alexander A Beckmann Matthias W MW Ekici Arif B AB Paul James J Brown Robert R Flanagan James M JM Harter Philipp P du Bois Andreas A Schwaab Ira I Hogdall Claus K CK Lundvall Lene L Olson Sara H SH Orlow Irene I Paddock Lisa E LE Rudolph Anja A Eilber Ursula U Dansonka-Mieszkowska Agnieszka A Rzepecka Iwona K IK Ziolkowska-Seta Izabela I Brinton Louise A LA Yang Hannah H Garcia-Closas Montserrat M Despierre Evelyn E Lambrechts Sandrina S Vergote Ignace I Walsh Christine S CS Lester Jenny J Sieh Weiva W McGuire Valerie V Rothstein Joseph H JH Ziogas Argyrios A Lubiński Jan J Cybulski Cezary C Menkiszak Janusz J Jensen Allan A Gayther Simon A SA Ramus Susan J SJ Gentry-Maharaj Aleksandra A Berchuck Andrew A Wu Anna H AH Pike Malcolm C MC Van Den Berg David D Terry Kathryn L KL Vitonis Allison F AF Ramirez Starr M SM Rider David N DN Knutson Keith L KL Sellers Thomas A TA Phelan Catherine M CM Doherty Jennifer A JA Johnatty Sharon E SE deFazio Anna A Song Honglin H Tyrer Jonathan J Kalli Kimberly R KR Fridley Brooke L BL Cunningham Julie M JM Goode Ellen L EL

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20140416 7

Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 7 ...[more]

PMID: 24740199

Similar Datasets

Project description:Background:The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods:We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results:Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions:Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality.

Project description:Paracrine signaling between tumor and surrounding stromal cells is critical for the maintenance of tumor microenvironment during ovarian cancer progression. Small extracellular vesicles (sEVs; exosomes in particular) are nano-sized vesicles secreted actively by many cells including tumor cells and are found to have fundamental roles in intercellular communication through shuttling functional RNAs. Although microRNAs (also called miRNAs or miRs), small non-coding RNAs regulating gene expression, are selectively accumulated in tumor sEVs and can mediate intercellular communication, the exact biological mechanisms underlying the functions of exosomal miRNAs in ovarian tumor angiogenesis remain unclear. In this study, sEVs were isolated from conditioned medium of the human ovarian carcinoma cell line SKOV-3 using ExoQuick Exosome Precipitation Solution, and characterized by scanning electron microscopy, dynamic light scattering, and immunoblotting. To elucidate the possible paracrine effects on ovarian tumor cell-derived sEVs (TD-sEVs), we investigated the angiogenesis-related signaling events triggered by TD-sEVs in endothelial cells. Due to the possible role in ovarian tumor pathogenesis, we focused on miR-141-3p which was detected to be enriched in TD-sEVs compared with their corresponding donor cells. We identified that sEV transfer of miR-141-3p considerably reduced the expression levels of cytokine-inducible suppressors of cytokine signaling (SOCS)-5 leading to up-regulated JAK-STAT3 pathway in endothelial cells. We also observed that sEV-shuttled miR-141-3p may up-regulate the expression of VEGFR-2 in endothelial cells which leads to promoting endothelial cell migration and angiogenesis. The putative role of miR-141-3p shuttled by TD-sEVs in regulating VEGFR-2 expression was demonstrated by the ability of anti-miR-141-3p to rescue the promoting effects of TD-sEVs on the expression of VEGFR-2 in endothelial cells. Our results also revealed that TD-sEVs trigger the intracellular reactive oxygen species (ROS)-dependent activation of NF-κB signaling in endothelial cells. Taken together, our findings propose a novel model in which sEV transfer of epithelial ovarian cancer-secreted miR-141-3p plays as a significant mediator of intercellular communication, promoting endothelial cell angiogenesis.

Dataset Information

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Publications

Variation in NF-κB signaling pathways and survival in invasive epithelial ovarian cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets