February 2009 Clinical Laboratory News: Diagnostic Profiles

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February 2009: Volume 35, Number 2

RNase III Enzymes Associated with Ovarian Cancer Survival  

New research indicates that low expression of the RNase III enzymes Dicer and Drosha are associated with poor survival in ovarian cancer (N Engl J Med 2008; 359:2641–2650). The results illuminate the role of RNA interference in the development of cancer, an aspect of the genetic mechanisms of the disease that has only been under investigation for about a decade. Further study of the proteins and their effect on the regulatory pathway in cancer cells could lead to more effective treatment for ovarian and other cancers. The researchers measured mRNA levels of Dicer and Drosha in 111 specimens of invasive epithelial ovarian cancer using quantitative RT-PCR and compared the results with clinical outcomes. Women whose tumors had low levels of Dicer mRNA had substantially reduced median overall survival; 2.33 years versus 9.25 years for those with tumors that had high levels. Similarly, women whose tumors had low levels of Drosha mRNA had an overall median survival of 2.74 years versus 7.92 years for those with tumors that had high levels.

The researchers validated their findings by comparing expression of Dicer and Drosha in previously reported microarray data from 132 patients with ovarian cancer. In this group of patients too, high expression of Dicer mRNA and Drosha mRNA were associated with increased survival. The investigators also examined whether the association existed in other tumor types and found that in both lung and breast cancer, high levels of Dicer mRNA were associated with increased survival, but not Drosha mRNA. The authors point out that high levels of the two mRNAs has not been associated uniformly with improved survival odds. Most notably, studies involving prostate and esophageal cancer have found that high levels of the two proteins are correlated with poor prognosis. Even as evidence is mounting that mRNA expression patterns vary among tumor types, the overall regulatory process related to RNA-interference is not entirely understood.

Rapid eGFR Decline Signals Mortality Risk in the Elderly

Rapid decline in eGFR is associated with an increased risk of both cardiovascular and all-cause mortality in older adults, independent of baseline eGFR and other demographic variables, according to a new analysis of Cardiovascular Health Study (CHS) data (Arch Intern Med 2008; 168:2212–2218). The findings suggest that eGFR may serve as an important prognostic tool in older adults, regardless of other pre-existing conditions.

Previous studies have demonstrated that chronic kidney disease—defined as an eGFR <60 mL/min/1.73m2—is a strong independent risk factor for cardiovascular disease and all-cause mortality, but few have correlated long-term changes in kidney function with future cardiovascular events. In this study, researchers determined the rates of both all-cause and cardiovascular mortality in CHS subjects who had two or three measurements of cystatin C and creatinine levels, using estimating equations to convert each value into an eGFR figure. They found that participants with rapid declines of eGFRcys of ≥3 mL/min/1.73m2 had a 50% increase in both all-cause and cardiovascular mortality, even after multivariate adjustments. Similarly, rapid decline of eGFRcreat after multivariate adjustments was associated with a >70% increase in both outcomes.

Although eGFRcys identified more patients with decline in kidney function than did eGFRcreat, participants with only eGFRcreat declines also had elevated mortality risk. This implies that eGFRcys has imperfect sensitivity for identifying those at high risk, and that the two measures may provide “complementary” risk assessment in older adults. Limitations of the study include lack of direct measurements of GFR, availability of only two measurements of cystatin C and creatinine in 85% of African American subjects, and lack of measurement of albuminuria at baseline. The authors conclude that their findings need to be confirmed in other cohorts of elderly adults.

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