Results published in NEJM links high levels of both to a median survival of 11 years and lower levels to 2.66 years.
The level of Dicer and Drosha proteins in a woman’s ovarian cancer are strongly associated with her likelihood of survival, according to a group of researchers. They found that women with high levels of the two proteins–vital to a cell’s gene-silencing machinery–had a median survival of 11 years. For those with low levels of either or both proteins, median survival was only 2.66 years.
“Dicer and Drosha are crucial for two types of RNA interference,” says senior author, Anil Sood, M.D., professor at The University of Texas M. D. Anderson. “We’ve found that when this machinery is disrupted, patient outcomes are poor.”
The researchers also analyzed gene-expression data in groups of lung and breast cancer patients and found similar associations with patient survival.
“Very consistently, we found that low levels of Dicer in particular are predictive of poor outcomes,” Sood explains. Molecular details of the raised risk for patients remain to be discovered, but it is likely that low levels of Dicer and Drosha permit some genes to continue functioning when they should be silenced.
The team measured expression levels of Dicer and Drosha in 111 invasive ovarian cancer tumors and then compared the results to the patients’ clinical outcomes. The initial findings were supported by a second gene-expression analysis in a different group of 132 ovarian cancer patients.
A statistical analysis of five risk factors for ovarian cancer showed that only low Dicer levels, high-grade tumors, and poor response to chemotherapy are independent predictors of survival. A genetic analysis of the Dicer and Drosha genes turned up mutations in both, but none that were associated with high or low levels of the proteins.
Analysis of 91 patients with lung cancer and 129 breast cancer patients found that only Dicer levels affected survival.
The researchers are now developing cancer drugs that deliver an siRNA via fatty nanoparticles to silence a specific cancer-causing gene. “We’ve found that another type of RNA, short hairpin RNA (shRNA) silences genes in a stable manner rather than the transient effects attributed to siRNA,” notes study senior co-author, Menashe Bar-Eli, Ph.D., professor of cancer biology.
However, animal models showed that these longer shRNA fragments could not silence genes in some cells. The authors found that about half of ovarian cancer cells either had low levels of Dicer and Drosha or lacked one or both proteins altogether.
A functional test of Dicer and Drosha for the project showed that shRNA does not work well with low levels of Dicer. When Dicer is low, siRNA still works. This suggests that for therapeutic purposes, siRNA might be the better option.
The study appears in the December 18 issue of the New England Journal of Medicine.
