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Micro-RNA Levels Higher in Aggressive Melanomas


 

CHICAGO — Micro-RNA-21 and micro-RNA-155 are expressed at significantly higher levels in primary malignant melanoma tumor samples than in samples from benign nevi—and in indeterminate melanocytic lesions with an aggressive histological phenotype, according to data presented at the American Society of Clinical Oncology annual meeting.

Samples from eight dermal nevi, 28 malignant melanomas, and 49 pathologically indeterminate melanocytic lesions were evaluated using real-time polymerase chain reaction. Investigators found a mean 7.6-fold increase in micro-RNA-21 expression (P = .0001) and a mean 13.3-fold increase (P = .0001) in micro-RNA-155 expression, compared with the benign nevus samples, reported Gregory B. Lesinski, Ph.D., of Ohio State University, Columbus.

Another potential biomarker—micro-RNA-21b—showed a trend toward increased expression, but the difference did not reach statistical significance in this small sample size (P = .07). However, micro-RNA-21b remains of interest, Dr. Lesinski noted.

Micro-RNA-21 and micro-RNA-155 also appear to be expressed at higher levels in certain indeterminate melanocytic lesions. Indeterminate lesions, including deep penetrating nevi, dysplastic nevi, and Spitz nevi, pose a particular challenge in that diagnosis and determination of the appropriate course of action are uncertain.

A false-positive diagnosis could lead to unnecessary treatment; a false-negative diagnosis could lead to undertreatment and increased risk of melanoma development.

In this study, expression of micro-RNA-21 and micro-RNA-155 was analyzed in indeterminate lesions with more than one mitosis per 10x high-power field.

When they were compared with those with less than one mitosis per 10x high-power field, there was significantly higher expression of micro-RNA-21 (P = .0005) and micro-RNA-155 (P = .04).

Melanocytic lesions that were greater than 1 mm in depth, compared with thinner lesions, also had significantly higher levels of micro-RNA-155 (P = .01), suggesting these might have more malignant potential; micro-RNA-21 was higher in the thicker lesions as well, but the difference did not reach statistical significance, Dr. Lesinski said.

In a subset of 13 patients with indeterminate lesions whose lesions were considered suspicious enough that the patients were sent for sentinel node biopsy, micro-RNA-21 and micro-RNA-155 expression were compared with expression in benign nevi—in both those that proved node positive and those that proved node negative.

Micro-RNA expression was significantly higher in the lesions from node-positive patients, compared with expression in benign nevi (mean 6.5-fold increase), than in node-negative patients, compared with expression in benign nevi (1.3-fold increase).

"Surprisingly, we didn't find the same relationship for micro-RNA-155; the data were highly variable [for micro-RNA-155] regardless of whether the patients were node negative or node positive," said Dr. Lesinski, who reported he has no disclosures relevant to the data he presented.

These data are "very preliminary," he added, noting that the sample size for this portion of the study is being expanded to include at least 50 patients to make a more accurate statistical determination about the expression of these micro-RNAs.

"Nonetheless, these data are very enticing to us, and they suggest that micro-RNA-21, at least, may in fact be a relevant marker that can be used to complement the traditional histological analyses used to diagnose these lesions," he said.

The expression of micro-RNAs—a group of more than 200 recently identified noncoding molecules considered to be a new class of oncogenes—is altered in many types of tumors.

This study is among the first to explore this expression in melanoma. Studies to further assess the potential value of micro-RNAs as diagnostic and prognostic tools in melanoma are ongoing, Dr. Lesinski said.

During a discussion of Dr. Lesinski's findings and those from other melanoma biomarker studies, Elizabeth Grimm, Ph.D., said they are part of a "fabulous set of new data."

Dr. Lesinski's findings regarding indeterminate lesions are particularly important given the therapeutic dilemma they pose, she said.

She expressed concern, however, about difficulty in determining whether micro-RNA expression is increased in melanomas, compared with indeterminate lesions. Differences were marked between melanoma and benign nevi, but based on her review of the data, it appears there was little difference in expression between melanoma and indeterminate lesions, Dr. Grimm said, adding that research regarding other micro-RNAs should continue.

She also noted that she is curious about whether there is a micro-RNA signature that adds value to the current staging system and markers commonly used, and whether micro-RNAs can be used independently of common diagnostic markers used by pathologists, such as MAGE, MART, and S100B.

While many questions remain, she applauded the research effort, noting that there are valid markers in other tumor types; thus, the "noble" efforts to identify molecular markers for melanoma are worthwhile. "We're not just dreaming—we will have them for melanoma some day," said Dr. Grimm of M.D. Anderson Cancer Center, Houston.

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