Document Detail

Dicer, Drosha, and outcomes in patients with ovarian cancer.
MedLine Citation:
PMID:  19092150     Owner:  NLM     Status:  MEDLINE    
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.
William M Merritt; Yvonne G Lin; Liz Y Han; Aparna A Kamat; Whitney A Spannuth; Rosemarie Schmandt; Diana Urbauer; Len A Pennacchio; Jan-Fang Cheng; Alpa M Nick; Michael T Deavers; Alexandra Mourad-Zeidan; Hua Wang; Peter Mueller; Marc E Lenburg; Joe W Gray; Samuel Mok; Michael J Birrer; Gabriel Lopez-Berestein; Robert L Coleman; Menashe Bar-Eli; Anil K Sood
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The New England journal of medicine     Volume:  359     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-12-18     Completed Date:  2009-01-07     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2641-50     Citation Subset:  AIM; IM    
Copyright Information:
2008 Massachusetts Medical Society
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MeSH Terms
Aged, 80 and over
Breast Neoplasms / genetics,  metabolism
Cell Line, Tumor
DEAD-box RNA Helicases / genetics,  metabolism*
DNA Mutational Analysis
Endoribonucleases / genetics,  metabolism*
Gene Expression Regulation, Neoplastic*
Kaplan-Meier Estimate
Lung Neoplasms / genetics,  metabolism
MicroRNAs / metabolism
Middle Aged
Multivariate Analysis
Mutation, Missense
Neoplasm Staging
Neoplasms, Glandular and Epithelial / genetics,  metabolism*,  mortality
Ovarian Neoplasms / genetics,  metabolism*,  mortality
RNA Interference*
RNA, Messenger / metabolism*
RNA, Small Interfering
Reverse Transcriptase Polymerase Chain Reaction
Ribonuclease III / genetics,  metabolism*
Treatment Outcome
Grant Support
CA109298/CA/NCI NIH HHS; CA110793/CA/NCI NIH HHS; P50 CA083639/CA/NCI NIH HHS; P50 CA083639/CA/NCI NIH HHS; P50 CA083639-090008/CA/NCI NIH HHS; P50 CA58207/CA/NCI NIH HHS; T32 CA101642/CA/NCI NIH HHS; U54 CA112970/CA/NCI NIH HHS; U54 CA112970/CA/NCI NIH HHS; U54 CA112970-05/CA/NCI NIH HHS
Reg. No./Substance:
0/MicroRNAs; 0/RNA, Messenger; 0/RNA, Small Interfering; EC 3.1.-/Endoribonucleases; EC protein, human; EC protein, human; EC III; EC RNA Helicases
Comment In:
N Engl J Med. 2008 Dec 18;359(25):2720-2   [PMID:  19092157 ]
Leuk Res. 2009 Aug;33(8):e127   [PMID:  19278725 ]
N Engl J Med. 2009 Mar 12;360(11):1150-1; author reply 1151   [PMID:  19279349 ]
Erratum In:
N Engl J Med. 2010 Nov 4;363(19):1877

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