Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer

被引:549
作者
Merritt, William M. [1 ]
Lin, Yvonne G. [1 ]
Han, Liz Y. [1 ]
Kamat, Aparna A. [1 ]
Spannuth, Whitney A. [1 ]
Schmandt, Rosemarie [1 ]
Urbauer, Diana [1 ]
Pennacchio, Len A. [2 ,3 ]
Cheng, Jan-Fang [2 ,3 ]
Nick, Alpa M. [1 ]
Deavers, Michael T. [1 ]
Mourad-Zeidan, Alexandra [1 ]
Wang, Hua [1 ]
Mueller, Peter [1 ]
Lenburg, Marc E. [4 ]
Gray, Joe W. [2 ]
Mok, Samuel [5 ]
Birrer, Michael J. [6 ]
Lopez-Berestein, Gabriel [1 ]
Coleman, Robert L. [1 ]
Bar-Eli, Menashe [1 ]
Sood, Anil K. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Unit 1362, Houston, TX 77230 USA
[2] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA
[3] US DOE, Joint Genome Inst, Walnut Creek, CA USA
[4] Boston Univ, Sch Med, Boston, MA 02118 USA
[5] Brigham & Womens Hosp, Boston, MA 02115 USA
[6] Ctr Canc Res, Bethesda, MD USA
基金
美国国家卫生研究院;
关键词
D O I
10.1056/NEJMoa0803785
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: We studied Dicer and Drosha, components of the RNA-interference machinery, in ovarian cancer. Methods: We measured messenger RNA (mRNA) levels of Dicer and Drosha in specimens of invasive epithelial ovarian cancer from 111 patients, using a quantitative reverse-transcriptase-polymerase-chain-reaction assay, and compared the results with clinical outcomes. Validation was performed with the use of published microarray data from cohorts of patients with ovarian, breast, and lung cancer. Mutational analyses of genomic DNA from the Dicer and Drosha genes were performed in a subgroup of ovarian-cancer specimens. Dicer-dependent functional assays were performed by means of in vitro transfection with small interfering RNA (siRNA) and short hairpin RNA (shRNA). Results: Levels of Dicer and Drosha mRNA correlated with the levels of expression of the corresponding protein and were decreased in 60% and 51% of ovarian-cancer specimens, respectively. Low Dicer expression was significantly associated with advanced tumor stage (P=0.007), and low Drosha expression with suboptimal surgical cytoreduction (P=0.02). Cancer specimens with both high Dicer expression and high Drosha expression were associated with increased median survival (>11 years, vs. 2.66 years for other subgroups; P<0.001). We found three independent predictors of reduced disease-specific survival in multivariate analyses: low Dicer expression (hazard ratio, 2.10; P=0.02), high-grade histologic features (hazard ratio, 2.46; P=0.03), and poor response to chemotherapy (hazard ratio, 3.95; P<0.001). Poor clinical outcomes among patients with low Dicer expression were validated in additional cohorts of patients. Rare missense mutations were found in the Dicer and Drosha genes, but their presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low Dicer expression. Conclusions: Our findings indicate that levels of Dicer and Drosha mRNA in ovarian-cancer cells have associations with outcomes in patients with ovarian cancer.
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收藏
页码:2641 / 2650
页数:10
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