Heterogeneous topographic profiles of kinetic and cell cycle regulator microsatellites in atypical (dysplastic) melanocytic nevi

Abstract

Atypical (dysplastic) melanocytic nevi are clinically heterogeneous malignant melanoma precursors, for which no topographic analysis of cell kinetic, cell cycle regulators and microsatellite profile is available. We selected low-grade atypical melanocytic nevi (92), high-grade atypical melanocytic nevi (41), melanocytic nevi (18 junctional, 25 compound) and malignant melanomas (16 radial growth phase and 27 vertical growth phase). TP53, CDKN2A, CDKN1A, and CDKN1B microsatellite patterns were topographically studied after microdissection; Ki-67, TP53, CDKN2A, CDKN1A, and CDKN1B expressions and DNA fragmentation by in situ end labeling for apoptosis were topographically scored. Results were statistically analyzed. A decreasing junctional-dermal marker expression gradient was observed, directly correlating with atypical melanocytic nevus grading. High-grade atypical melanocytic nevi revealed coexistent TP53-CDKN2A-CDKN1B microsatellite abnormalities, and significantly higher junctional Ki67-TP53 expression (inversely correlated with CDKN1A-CDKN1B expression and in situ end labeling). Malignant melanomas showed coexistent microsatellite abnormalities (CDKN2A-CDKN1B), no topographic gradient, and significantly decreased expression. Melanocytic nevi and low-grade atypical melanocytic nevi revealed sporadic junctional CDKN2A microsatellite abnormalities and no significant topographic kinetic differences. High-grade atypical melanocytic nevi accumulate junctional TP53-CDKN1A-CDKN1B microsatellite abnormalities, being progression TP53-independent and better assessed in the dermis. Melanocytic nevi and low-grade atypical melanocytic nevi show low incidence of microsatellite abnormalities, and kinetic features that make progression unlikely.

Tumor Heterogeneity: Mechanisms and Bases for a Reliable Application of Molecular Marker Design

“…The complexity of tumor evolution is further influenced by the ongoing alterations of tumor microenvironment associated with tumor progression, [33] which are likely to alter the selective pressures experienced by tumor cells. Therefore, at the microscopic level, tumor evolution is likely to be non-linear, and substantial genetic heterogeneity is expected in tumor cell populations [10,23,30,31,34]. …”

“…Several intraepithelial foci showed more alterations than matched invasive foci, suggesting a more extensive genetic evolution for the former and supporting multifocality and independent clonal evolution of these coexistent carcinomas. The accumulation of genetic abnormalities in intraepithelial carcinomas is consistent with an advanced molecular stage and progression, along with topographic genetic heterogeneity [23,25,30,31,34,167]. Cancer cells are able to survive and proliferate only at specific secondary sites where there is an ideal environment that releases molecular mediators suitable for that type of cancer cells, still represents a main conceptual model of metastasis in modern cancer research [3,173–175].…”

“…Moreover, spatial constraints that exist within a tumor can slow down the achievement of clonal dominance by substantially inhibiting competition among different tumor cell clones [9,10,22,23,34,166,217]. The importance of spatial constraints for the emergence and maintenance of clonal heterogeneity is supported by experimental observations in colon cancer as well as in silico modeling [218].…”

“…There is increasing evidence that miRNAs have potential not only to facilitate the determination of diagnosis and prognosis and the prediction of response to treatment, but also to act as therapeutic targets and replacement therapies [267,268]. The biological heterogeneity in neoplasm and precancerous lesions would potentially make more difficult these assessments [34,269,270]. We only have to consider that deep tumor compartments provide more accurate prognostic information in melanomas and dermal compartments rather than the junctional compartments better define dysplastic melanocytic lesions.…”

Practical advice regarding problematic pigmented lesions

“…6 In an early article, Elder et al 7 used ''atypical nevus'' and ''dysplastic nevus'' as synonyms, and the two terms continue to be used as synonyms by some authors. 8,9 Although the term ''dysplastic nevus'' is attributed to Clark, it has been noted that similar familial atypical moles had already described by Norris in 1820 and by Cawley in 1952. 10 One of the reviewers of this article noted that in practice, Dr Clark commented on ''melanocytic dysplasia of the type which may be seen in the dysplastic nevus syndrome.''…”