Clonal relationships between epidermotropic metastatic melanomas and their primary lesions: a loss of heterozygosity and X-chromosome inactivation-based analysis

Abstract

Loss of heterozygosity (LOH) has previously been demonstrated at multiple chromosome microsatellites in primary and metastatic melanomas. Epidermotropic metastases of melanoma are unique in their varied histopathologic appearance, which can mimic a primary lesion. Our objective was to compare LOH profiles in primary and epidermotropic metastatic melanoma to delineate their clonal relationship. We examined the pattern of allelic loss in the primary melanomas of nine patients in addition to the 21 corresponding epidermotropic metastatic melanomas (average 2.3 metastases per patient). DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser capture microdissection. Eight DNA microsatellite markers on six different chromosomes were analyzed: D1S214 (1p), D6S305 (6q), D9S171 (9p), D9S157 (9p), IFNA (9p), D10S212 (10q), D11S258 (11q), D18S70 (18q). In addition, X-chromosome inactivation analysis was performed in tumors from four women. LOH was seen in 67% (6/9) of primary melanomas and 81% (17/21) of epidermotropic metastatic melanomas. The most frequent allelic losses in informative cases occurred at 10q (33%), 9p (22%), and 11q (22%) in primary melanomas, and at 10q (50%), 1p (44%), and 6q (39%) in epidermotropic metastatic melanomas. Primary lesions demonstrating LOH had concordant allelic loss in at least one locus in a corresponding epidermotropic metastatic melanoma in 83% (5/6) of cases. X-chromosome analysis showed nonrandom inactivation in 75% (3/4) and 71% (5/7) of primary melanoma and epidermotropic metastatic melanoma cases, respectively. Our LOH and X-chromosome inactivation analysis data suggest that epidermotropically metastatic melanomas are clonally related to their primary lesion in many cases. Our data also indicated that some cases diagnosed as epidermotropic metastatic melanoma might be divergent clones or new primaries rather than metastatic disease.

AIM1 and LINE-1 Epigenetic Aberrations in Tumor and Serum Relate to Melanoma Progression and Disease Outcome

“…Trent et al demonstrated that melanoma lines directly introduced with a normal copy of chromosome 6 lost their ability to form tumors in nude mice, and the loss of chromosome 6 from melanoma microcell hybrids resulted in reversion to tumorigenicity of these cells(Trent et al , 1990). High frequency of loss of heterozygosity(LOH) of chromosome 6q has also been reported in melanoma lines and tissues(Bahrami et al , 2007; Fujiwara et al , 1999; Stark and Hayward, 2007). However, it still remains unclear which key genes are specifically involved in melanoma progression in the 6q21-22 region of melanomas.…”

Comprehensive histopathological comparison of epidermotropic/dermal metastatic melanoma and primary nodular melanoma

“…The occurrence of multiple lesions in the vicinity of the primary melanoma site also provides compelling clinical evidence for metastases. However, when clinicopathological correlation fails to elucidate the primary versus metastatic nature of a lesion, molecular studies may be needed to facilitate more accurate staging …”

Epidermotropic metastatic melanoma with perilesional depigmentation in an Indian male

“…However, variable patterns within the same case indicate that, while some epidermotropic metastatic melanomas are clonally related to the primary, others are of independent origin. [13]…”