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Enzymes Predict Ovarian Cancer Outcomes

By Michael Smith, North American Correspondent, MedPage Today
Published: December 17, 2008
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
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HOUSTON, Dec. 17 -- Levels of two enzymes in ovarian cancer tissue are strongly associated with survival, researchers here found.
Action Points  
  • Explain to interested patients that there are few molecular markers that help doctors form a prognosis in cases of ovarian cancer.

  • Note that this study suggests that levels of two enzymes in the cancer tissue can provide such guidance.

High levels of both enzymes -- dubbed Dicer and Drosha -- are associated with survival that's nearly five times longer than is seen with lower levels, according to Anil Sood, M.D., of M. D. Anderson Cancer Center, and colleagues.

In a cohort study, women with high levels of both enzymes had a median survival of more than 11 years, Dr. Sood and colleagues said in the Dec. 18 issue of the New England Journal of Medicine.

In contrast, women whose tumors had one of the three other possible expression patterns -- high Dicer and low Drosha, for example -- median survival was 2.66 years, the researchers found.

The two enzymes, microRNAs (miRNAs), play a role in what's called RNA interference, which cells use to turn genes off, according to Dr. Sood. "We've found that when this (gene-silencing) machinery is disrupted, patient outcomes are poor," he said.

The miRNAs are a large class of small, regulatory, noncoding RNAs in plants and animals that inhibit gene expression by binding to imperfect complementary sites within the three untranslated regions of their target -- messenger RNA transcripts, the researchers said.

The findings come from an analysis of tumor tissue from a cohort of 111 patients, using a quantitative reverse transcriptase-polymerase-chain-reaction assay.

The researchers defined low and high expression of the two enzymes by calculating the ratio of their expression in cancer tissue to the expression seen in 11 benign ovarian epithelial tissue samples.

For both enzymes, low expression was defined as a ratio of less than one.

Analysis showed that 60% of women in the cohort had low Dicer levels and 51% had decreased Drosha, while in 39% of specimens, levels of both were decreased.

When the researchers looked at clinical outcomes for the women in the study, they found that -- in univariate analyses -- neither Dicer nor Drosha levels were associated with age, tumor grade, or response to chemotherapy.

On the other hand, low Dicer levels were significantly associated (at P=0.007) with advanced tumor stage and low Drosha levels were associated with suboptimal cytoreductive surgery (at P=0.02).

Median overall survival was markedly reduced among women whose tumor had low Dicer levels -- 2.33 years versus 9.25 years for those with high levels, which was significant at P<0.001.

The same was true for low versus high levels of Drosha -- 2.74 years compared with 7.92 years, which was significant at P=0.008, the researchers reported.

In a multivariate analysis, three factors were found to independently predict reduced disease-specific survival:

  • Low Dicer expression yielded a hazard ratio of 2.10, which was significant at P=0.02
  • High-grade histologic features led to a hazard ratio of 2.46, significant at P=0.03
  • Poor response to chemotherapy gave a hazard ratio of 3.95, significant at P<0.001

In an independent cohort of ovarian cancer patients, low Dicer levels were also linked to poor clinical outcomes.

Exactly why outcomes should be worse remains to be clarified, Dr. Sood said, but it's likely that low levels of Dicer and Drosha allow some genes to continue functioning when they should be shut off.

"RNA interference has only been known for about a decade," he said. "The components of the machinery, what it does in cancer, and how it affects outcomes and therapy are not fully known."

In ovarian cancer, there are "few if any" molecular signposts that can predict outcome and potentially guide therapy, according to Frank Slack, Ph.D., and Joanne Weidhaas, M.D., Ph.D., both of Yale University.

The value of this study, they said in an accompanying editorial, is that it offers "evidence for a simple mechanism" that might help doctors with prognosis and potentially with treatment.

The findings are part of a "new era in the understanding of gene regulation in diseases such as cancer," they said.

"Not only does this work provide useful prognostic markers," they said, but it may also form "the first steps toward designing strategies to target microRNA-processing mechanisms with the goal of improving outcomes."

The study was supported by the National Cancer Institute, the Ovarian Cancer Research Fund, the University of Texas M.D. Anderson Cancer Center, the NIH, the Gynecologic Cancer Foundation, the Zarrow Foundation, the Betty Ann Asche Murray Distinguished Professorship, the Marcus Foundation, and the U.S. Department of Energy.

Dr. Sood reported no conflicts.

Dr. Slack reported holding two pending patents for the use of microRNAs as potential therapeutic and diagnostic markers in cancer.

Dr. Weidhaas reported two pending patents for the use of microRNAs in predicting the risk of ovarian cancer and response to chemotherapy.

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