Block Matthew S, Charbonneau Bridget, Vierkant Robert A, Fogarty Zachary, Bamlet William R, Pharoah Paul D P, Rossing Mary Anne, Cramer Daniel, Pearce Celeste Leigh, Schildkraut Joellen, Menon Usha, Kjaer Susanne K, Levine Douglas A, Gronwald Jacek, Culver Hoda Anton, Whittemore Alice S, Karlan Beth Y, Lambrechts Diether, Wentzensen Nicolas, Kupryjanczyk Jolanta, Chang-Claude Jenny, Bandera Elisa V, Hogdall Estrid, Heitz Florian, Kaye Stanley B, Fasching Peter A, Campbell Ian, Goodman Marc T, Pejovic Tanja, Bean Yukie T, Hays Laura E, Lurie Galina, Eccles Diana, Hein Alexander, Beckmann Matthias W, Ekici Arif B, Paul James, Brown Robert, Flanagan James M, Harter Philipp, du Bois Andreas, Schwaab Ira, Hogdall Claus K, Lundvall Lene, Olson Sara H, Orlow Irene, Paddock Lisa E, Rudolph Anja, Eilber Ursula, Dansonka-Mieszkowska Agnieszka, Rzepecka Iwona K, Ziolkowska-Seta Izabela, Brinton Louise A, Yang Hannah, Garcia-Closas Montserrat, Despierre Evelyn, Lambrechts Sandrina, Vergote Ignace, Walsh Christine S, Lester Jenny, Sieh Weiva, McGuire Valerie, Rothstein Joseph H, Ziogas Argyrios, Lubiński Jan, Cybulski Cezary, Menkiszak Janusz, Jensen Allan, Gayther Simon A, Ramus Susan J, Gentry-Maharaj Aleksandra, Berchuck Andrew, Wu Anna H, Pike Malcolm C, Van Den Berg David, Terry Kathryn L, Vitonis Allison F, Ramirez Starr M, Rider David N, Knutson Keith L, Sellers Thomas A, Phelan Catherine M, Doherty Jennifer A, Johnatty Sharon E, deFazio Anna, Song Honglin, Tyrer Jonathan, Kalli Kimberly R, Fridley Brooke L, Cunningham Julie M, Goode Ellen L
Authors' Affiliations: Departments of Medical Oncology.
Health Sciences Research, Division of Epidemiology;
Cancer Epidemiol Biomarkers Prev. 2014 Jul;23(7):1421-7. doi: 10.1158/1055-9965.EPI-13-0962. Epub 2014 Apr 16.
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.
上皮性卵巢癌（EOC）的生存率受宿主免疫反应影响，但影响预后的炎症和免疫的关键基因决定因素尚不清楚。核因子-κB（NF-κB）转录因子家族在许多免疫和炎症反应中发挥重要作用，包括对癌症的反应。我们研究了卵巢癌协会联盟中10084例浸润性EOC患者（5248例高级别浆液性、1452例子宫内膜样、795例透明细胞和661例黏液性）中NF-κB家族210个基因的常见遗传变异。使用Cox回归对所有患者以及主要组织学类型评估基因型与总生存率之间的关联，并对已知的预后因素进行调整，同时校正多重检验（统计学显著性阈值，P < 2.5×10⁻⁵）。对单一组织学类型的患者进行评估时，结果具有统计学显著性。关键关联包括黏液性EOC患者中半胱天冬酶募集结构域家族成员11（CARD11）rs41324349（风险比[HR]，1.82；95%置信区间[CI]，1.41 - 2.35；P = 4.13×10⁻⁶）以及子宫内膜样EOC患者中肿瘤坏死因子受体超家族成员13B（TNFRSF13B）rs7501462（HR，0.68；95%CI，0.56 - 0.82；P = 2.33×10⁻⁵）。其他值得注意的关联包括高级别浆液性EOC患者中肿瘤坏死因子受体相关因子2（TRAF2）rs17250239（HR，0.84；95%CI，0.77 - 0.92；P = 6.49×10⁻⁵）以及透明细胞EOC患者中磷脂酶Cγ1（PLCG1）rs11696662（HR，0.43；95%CI，0.26 - 0.73；P = 4.56×10⁻⁴）。这些关联突出了与宿主炎症和免疫相关的基因在调节不同EOC组织学类型临床结局方面的潜在重要性。
