September 2008 • www.skinandallergynews.com Cutaneous Oncology 29 Micro-RNA Levels Higher in Aggressive Melanomas BY SHARON WORCESTER A false-positive diagnosis could lead to positive patients, compared with expres- tools in melanoma are ongoing, Dr. Southeast Bureau unnecessary treatment; a false-negative sion in benign nevi (mean 6.5-fold in- Lesinski said. diagnosis could lead to undertreatment crease), than in node-negative patients, During a discussion of Dr. Lesinski’s C HICAGO — Micro-RNA-21 and mi- and increased risk of melanoma devel- compared with expression in benign nevi findings and those from other melanoma cro-RNA-155 are expressed at significant- opment. (1.3-fold increase). biomarker studies, Elizabeth Grimm, ly higher levels in primary malignant In this study, expression of micro-RNA- “Surprisingly, we didn’t find the same re- Ph.D., said they are part of a “fabulous set melanoma tumor samples than in samples 21 and micro-RNA-155 was analyzed in in- lationship for micro-RNA-155; the data of new data.” from benign nevi—and in indeterminate determinate lesions with more than one were highly variable [for micro-RNA-155] Dr. Lesinski’s findings regarding inde- melanocytic lesions with an aggressive mitosis per 10x high-power field. regardless of whether the patients were terminate lesions are particularly impor- histological phenotype, according to data When they were node negative or tant given the therapeutic dilemma they presented at the American Society of compared with those ‘Micro-RNA-21, at least, node positive,” said pose, she said. Clinical Oncology annual meeting. with less than one Dr. Lesinski, who re- She expressed concern, however, about Samples from eight dermal nevi, 28 mitosis per 10x high- may in fact be a relevant ported he has no dis- difficulty in determining whether micro- malignant melanomas, and 49 pathologi- power field, there marker that can be used to closures relevant to RNA expression is increased in cally indeterminate melanocytic lesions was significantly the data he present- melanomas, compared with indetermi- were evaluated using real-time poly- higher expression of complement the traditional ed. nate lesions. Differences were marked be- merase chain reaction. Investigators found micro-RNA-21 (P = histological analyses used These data are tween melanoma and benign nevi, but a mean 7.6-fold increase in micro-RNA-21 .0005) and micro- “very preliminary,” based on her review of the data, it appears expression (P = .0001) and a mean 13.3- RNA-155 (P = .04). to diagnose these lesions.’ he added, noting that there was little difference in expression be- fold increase (P = .0001) in micro-RNA- Melanocytic le- the sample size for tween melanoma and indeterminate le- 155 expression, compared with the benign sions that were greater than 1 mm in this portion of the study is being expand- sions, Dr. Grimm said, adding that re- nevus samples, reported Gregory B. depth, compared with thinner lesions, ed to include at least 50 patients to make search regarding other micro-RNAs Lesinski, Ph.D., of Ohio State University, also had significantly higher levels of mi- a more accurate statistical determination should continue. Columbus. cro-RNA-155 (P = .01), suggesting these about the expression of these micro- She also noted that she is curious about Another potential biomarker—micro- might have more malignant potential; RNAs. whether there is a micro-RNA signature RNA-21b—showed a trend toward in- micro-RNA-21 was higher in the thicker “Nonetheless, these data are very entic- that adds value to the current staging sys- creased expression, but the difference did lesions as well, but the difference did not ing to us, and they suggest that micro- tem and markers commonly used, and not reach statistical significance in this reach statistical significance, Dr. Lesinski RNA-21, at least, may in fact be a relevant whether micro-RNAs can be used inde- small sample size (P = .07). However, mi- said. marker that can be used to complement pendently of common diagnostic markers cro-RNA-21b remains of interest, Dr. In a subset of 13 patients with indeter- the traditional histological analyses used to used by pathologists, such as MAGE, Lesinski noted. minate lesions whose lesions were con- diagnose these lesions,” he said. MART, and S100B. Micro-RNA-21 and micro-RNA-155 also sidered suspicious enough that the pa- The expression of micro-RNAs—a While many questions remain, she ap- appear to be expressed at higher levels in tients were sent for sentinel node biopsy, group of more than 200 recently identified plauded the research effort, noting that certain indeterminate melanocytic le- micro-RNA-21 and micro-RNA-155 ex- noncoding molecules considered to be a there are valid markers in other tumor sions. Indeterminate lesions, including pression were compared with expression new class of oncogenes—is altered in types; thus, the “noble” efforts to identify deep penetrating nevi, dysplastic nevi, in benign nevi—in both those that proved many types of tumors. molecular markers for melanoma are and Spitz nevi, pose a particular chal- node positive and those that proved node This study is among the first to explore worthwhile. “We’re not just dreaming— lenge in that diagnosis and determination negative. this expression in melanoma. Studies to we will have them for melanoma some of the appropriate course of action are Micro-RNA expression was signifi- further assess the potential value of mi- day,” said Dr. Grimm of M.D. Anderson uncertain. cantly higher in the lesions from node- cro-RNAs as diagnostic and prognostic Cancer Center, Houston. ■ Gene Loss May Explain Gender Differences in Melanoma BY SHARON WORCESTER vival (P = .015), reported Dr. Spatz of Institut Gustave cess risk of death of 1.87, compared with women with Southeast Bureau Roussy in Villejuif, France. melanoma. Further investigation to identify any particular gene or “We can conclude that there is a very specific pattern C HICAGO — A specific pattern of X and Y chromo- genes that fulfilled the criteria of being located on the X of X and Y chromosome losses associated with melanoma some losses—and in particular the loss of an important chromosome in women and escaping inactivation of X progression … and that PPP2R3B appears from this tumor-suppression gene—was shown in a recent study to chromosome, as well as being located on the Y chromo- study to be a very important tumor suppression gene be associated with melanoma progression. some in men, showed that only the PPP2R3B gene, also whose loss is associated with tumor progression. This “very new and very unexpected finding” could know as PR48, did so. “Does this explain the gender effect? Maybe if indeed help explain gender differences that are seen in The normalized expression of the gene, which is lo- we show that there is a differential frequency of inacti- melanoma, such as the increased cated on Xp22 in women and on Yp11 vated X chromosome in females, as compared with Y risk of death in men with mel- ‘PPP2R3B appears from in men was found to be associated chromosome—but this is still an open question,” Dr. anoma, compared with women with with distant metastasis-free survival Spatz said. melanoma, Dr. Alan Spatz said at the this study to be a very at a “totally unexpected level of sig- In a discussion of the findings, Elizabeth Grimm, American Society of Clinical On- important tumor nificance,” (P = .0007), after adjusting Ph.D., a professor at the University of Texas M.D. An- cology annual meeting, where he for clinical and pathologic prognostic derson Cancer Center, Houston, called these and other presented the findings. suppression gene whose variables, including gender, age, ul- emerging data a “snapshot of finest biomarker work in Frozen sections from 48 mel- loss is associated with ceration, and thickness, Dr. Spatz said. melanoma at this time.” Dr. Spatz’s work is particularly anomas—taken from 32 women and tumor progression.’ PR48 is a lesser-known subunit of a provocative, she said. 16 men with a median follow-up of well-known and very important gene She asked, however, how—given the findings—one 4 years—were analyzed as part of a (serine/threonine protein phosphatase would explain that the incidence of melanoma in young European Organisation for Research and Treatment of 2A) which he described as “kind of a gatekeeper in cell women is higher than that in young men. The increased Cancer (EORTC) study. Analyses of DNA and mRNA biology,” he said. incidence in men only begins to become evident around were conducted; the end point was distant metastasis- PR48 mediates the dephosphorylation of CDC6 by age 50 years, she noted, questioning whether other free survival. phosphatase 2A and controls initiation of DNA repli- lifestyle parameters are in play. A significant correlation was found between DNA cation in human cancer cells, especially melanoma, he “Just food for thought,” she said. copy number and mRNA level for 1,455 genes (P less than explained. Dr. Grimm also noted that it would be interesting, .05). In the women’s samples, losses in the X chromosome The findings, along with those from other ongoing should the findings be validated in the ongoing studies were significantly associated with distant metastasis-free studies that are designed to help improve understand- that Dr. Spatz mentioned, to see how they might change survival (P = .009), and the affected X chromosome was ing of PPP2R3B biology, could potentially provide bio- the course of treatment or provide prognostic infor- always the inactive X. logic clues regarding gender differences in melanoma mation, and to determine whether some form of gene In the men, losses in the Y chromosome were sig- progression and survival; the gender effect in melanoma therapy to redeliver the X and Y chromosome losses nificantly associated with distant metastasis-free sur- is strong—men have been shown to have a relative ex- could be developed.