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Previous Volume 359:2641-2650 December 18, 2008 Number 25 Next

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ABSTRACT

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.

Source Information

From the University of Texas M.D. Anderson Cancer Center, Houston (W.M.M., Y.G.L., L.Y.H., A.A.K., W.A.S., R.S., D.U., A.M.N., M.T.D., A.M.-Z., H.W., P.M., G.L.-B., R.L.C., M.B.-E., A.K.S.); Lawrence Berkeley National Laboratory, Berkeley, CA (L.A.P., J.-F.C., J.W.G.); the U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA (L.A.P., J.-F.C.); Boston University School of Medicine (M.E.L.) and Brigham and Women's Hospital (S.M.) — both in Boston; and the Center for Cancer Research, Bethesda, MD (M.J.B.).

Address reprint requests to Dr. Sood at the Departments of Gynecologic Oncology and Cancer Biology, M.D. Anderson Cancer Center, Unit 1362, P.O. Box 301439, Houston, TX 77230-1439, or at asood{at}mdanderson.org.

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Related Letters:

Dicer and Drosha in Ovarian Cancer
Köbel M., Gilks C. B., Huntsman D. G., Merritt W. M., Urbauer D. L., Sood A. K.
Extract | Full Text | PDF  
N Engl J Med 2009; 360:1150-1151, Mar 12, 2009. Correspondence

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