Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma

Abstract

Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays (N = 38 samples) to reveal organ specific alterations. Results were partly completed by proteomic analysis. A significant increase of high-copy number gains was found in an organ-specific manner, whereas copy number losses were predominant in brain metastases, including the loss of numerous DNA damage response genes. Amplification of many immune genes was also observed, several of them are novel in melanoma, suggesting that their ectopic expression is possibly underestimated. This “immunogenic mimicry” was exclusive for lung metastasis. We also provided evidence for the possible autocrine activation of c-MET, especially in brain and lung metastases. Furthermore, frequent loss of 9p21 locus in brain metastases may predict higher metastatic potential to this organ. Finally, a significant correlation was observed between BRAF gene copy number and mutant allele frequency, mainly in lung metastases. All of these events may influence therapy efficacy in an organ specific manner, which knowledge may help in alleviating difficulties caused by resistance.

Newly identified form of phenotypic plasticity of cancer: immunogenic mimicry

“…(unpublished data) Meanwhile, in most of these cases, CNV was not demonstrated to be responsible for such an ectopic expression; therefore, epigenetic mechanisms must be considered as a driving factor. In a recent study addressing human melanoma metastases, genome-wide CNV analysis revealed copy number gain of several CD genes including new ones: CD1a/e, CD48, CD84, CD93, CD209, CD217, and CD247, as well as known ones such as CD36, CD40, CD47, CD70, CD160, CD172, CD320, and IDO1 [96]. In all those instances, mRNA and protein expressions have been validated in an independent dataset.…”

“…In all those instances, mRNA and protein expressions have been validated in an independent dataset. It is of note that the majority of these CD gene amplifications were detected in lung metastases, to a lesser extent in liver ones, and rarely observed in brain metastases, suggesting a unique clonal selection [96]. The pertinent literature on ectopic immune cell gene expressions in cancer is summarized on Table 1.…”

“…The pertinent literature on ectopic immune cell gene expressions in cancer is summarized on Table 1. It is important that only 9/26 of those genes are unique to melanoma [96]; therefore, the majority of them can be found in various common cancer types.…”

Reducing MYC's transcriptional footprint unveils a good prognostic gene signature in melanoma

“…Notably, in melanoma, as in most solid tumors, hypoxia is associated with aggressiveness and metastases ( Kalaora et al 2022 ). The fraction of genome altered is the percentage of genome that has been affected by copy number gains or losses, and it has recently been shown that, in melanoma, it increases in visceral metastases compared with their respective primary tumors ( Papp et al 2021 ).…”

The role of tumor-associated macrophages and soluble mediators in pulmonary metastatic melanoma

“…The typical characteristics of cutaneous melanoma are early dissemination and subsequent metastatic colonization of multiple organs, for instance, lymph nodes, lung, liver, bone, and brain are common metastatic sites of skin melanoma (3). It's worth noting that metastatic melanoma is the main cause of its high mortality and among multiple organs that may be colonized by cutaneous melanoma, the lung is one of the most common distant metastatic sites of melanoma (3)(4)(5)(6). The incidence of pulmonary metastasis of melanoma accounts for 5% of all malignant metastases, and the mortality rate of pulmonary metastasis of melanoma is also very high (7).…”