Comparison of Genetic Profiles Between Primary Melanomas and their Metastases Reveals Genetic Alterations and Clonal Evolution During Progression

Abstract

To examine for the genetic basis of metastatic progression in cutaneous melanoma, we have compared loss of heterozygosity (LOH) of several selected chromosome regions that are implicated in the initiation and progression of melanoma, and alterations of the p16INK4a gene in 14 pairs of primary tumor and synchronous or asynchronous metastasis excised from the same patients. The most frequent genetic alteration during metastatic progression detected was the loss of p16INK4a protein expression (four of 14 cases), whereas no somatic p16INK4a gene mutations were found in any primary or metastatic tumors. LOH analyses showed that most of the chromosome losses including 6q, 8p, 9p, 9q, and 18q were shared between primary tumors and their metastases. Nevertheless, LOH of 6q and 11q and LOH of 7q not detected in primary tumors were, respectively, observed in two lymph node metastases. These results suggest that loss of p16INK4a protein expression (but not p16INK4a gene mutation) and the losses of chromosome arms 6q, 7q, and 11q play an important role in the acquisition of metastatic potential in sporadic melanoma. Furthermore, comparison of genetic profiles between the primary tumor and its metastasis revealed in several cases that heterogenous tumor cell populations might already exist at the early stage of tumorigenesis and evolve independently in the primary tumor and its metastasis, strongly suggesting that metastatic progression of sporadic melanoma is not accounted for by a linear progression model.

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

“…In the current study, LOH at 1p and 6q was also a frequent finding in the epidermotropic metastatic melanomas confirming past investigations that have found frequent LOH at these sites in various subtypes of melanoma metastases. 19,38 In conclusion, we found that primary melanomas and their epidermotropic metastatic melanomas have LOH at various microsatellite regions on chromosomes 1p, 6q, 9p, 10q, 11q, and 18q. Additionally, nonrandom X-chromosome inactivation is seen in the majority of cases in women.…”

“…Many reports have shown that primary melanomas most frequently demonstrate LOH on chromosome 9 in the region of a well-known tumor suppressor gene, p16INK4. 19,21,38,40,41 Interestingly, this region was the second most frequent site of LOH in our primary melanomas, with LOH at 10q found most frequently. LOH at 10q was also found most frequently and in higher proportion in the epidermotropic metastatic melanomas.…”

“…[19][20][21][37][38][39] However, the present study is the first to assess clonal genetic relationships between primary melanomas and an uncommon subtype of metastasis, the epidermotropic metastatic melanoma. The importance of studying this relationship is underscored by the fact that histopathology alone may be insufficient to distinguish an epidermotropic metastatic melanoma from a new primary lesion.…”

“…Further divergence of the clone may result in subpopulations of neoplastic cells, some of which gain the capacity to metastasize. [13][14][15][16][17] Although genetic heterogeneity is the norm in melanoma, [18][19][20][21][22] it would be expected that a primary melanoma and its metastases would share at least one or more genetic alterations. Studies to date have shown that loss of heterozygosity (LOH) on 9p and 10q has been associated with early-stage primary disease, whereas LOH on 6q, 1p, 8q, and 11q has been associated with progression and metastasis.…”

“…Studies to date have shown that loss of heterozygosity (LOH) on 9p and 10q has been associated with early-stage primary disease, whereas LOH on 6q, 1p, 8q, and 11q has been associated with progression and metastasis. 19 In this report, we studied primary melanomas and their corresponding epidermotropic metastases using LOH analysis and X-chromosome inactivation analysis to delineate their clonal relationship.…”