Enzyme inventory affects ovarian cancer outlook

Amounts of two compounds needed for shutting down genes might clarify a patient’s prognosis

Women with rapidly lethal ovarian cancer are more likely to harbor tumors lacking a normal complement of two enzymes that facilitate the silencing of genes, a new study shows. Meanwhile, patients who survive significantly longer tend to have ample supplies of both compounds, scientists report in the Dec. 18 New England Journal of Medicine.

Data on patients with other cancers also linked better survival to adequate levels of one of these enzymes, the researchers find

If confirmed, the new finding might enable doctors to make more precise prognoses for patients with ovarian cancer and possibly other malignancies by testing for these enzymes in tumor tissue. The work may also contribute to a further understanding of RNA interference, in which microRNAs or another type of genetic fragment called small interfering RNAs stop biosynthesis of proteins in a cell.

Dicer and Drosha, the enzymes measured in the new study, facilitate the RNA interference process. Human cells make thousands of kinds of RNA fragments, which scientists believe serve as safeguards that keep abnormal proteins — or the wrong amount of them — from being manufactured from their gene blueprints.

Dicer and Drosha also appear in normal cells, where the enzymes perform their work unnoticed much of the time. “We are trying to understand why this machinery is altered in cancer cells,” says Anil Sood, a gynecologic oncologist at the University of Texas M.D. Anderson Cancer Center in Houston.

Earlier work suggested that in cancerous cells a lack of Dicer might contribute to the malignant nature of the cells.

Sood and his colleagues analyzed Dicer and Drosha concentrations in ovarian tumor tissue from 111 patients, dividing the samples into those that contained high or low levels of the enzymes. The team found that 39 percent of women had the lower amounts of both enzymes.

On average, women with higher levels of both enzymes survived more than11 years from the time of their diagnosis, whereas those with lower amounts of Dicer and Drosha lived 2.7 years on average, the team reports.

When the scientists accounted for differences between the groups that included age, stage of the cancer and initial response to chemotherapy, women with ample Dicer and Drosha still showed a median survival that was four times longer than those with a shortage of the enzymes.

The researchers then analyzed information obtained from other sets of patients with lung, breast and ovarian cancer. The team found that shortages of both enzymes led to bleaker survival prospects in the ovarian cancer group. But only low Dicer levels worsened survival in people with the other two cancers.

Apparently, low amounts of these enzymes allow some genes to remain switched on and encode proteins when they would be better off shut down, Sood says.

The study “provides evidence for a simple mechanism, based on the biologic characteristics of microRNAs, for formulating a prognosis and potentially guiding therapy in ovarian cancer,” say Frank Slack and Joanne Weidhaas of Yale University, writing in the same issue of NEJM.

The researchers are still missing an explanation for the shortage of Dicer and Drosha in some of these cancer patients in the first place. “I wish we had the exact answer,” says Sood. He and his team found mutations in genes encoding the enzymes, but these defects didn’t seem related to Dicer or Drosha amounts, he says.

The long-term hope is to harness these RNA fragments as drugs to fight cancer, but that research is still at a theoretical stage, he says.

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