The skin cuteneous melanoma proteomeMalignant melanoma is the leading cause of skin-related death in Caucasians, but rare in populations with darker pigmented skin color. The incidence has increased dramatically during the last decades, with an almost four-fold increase in the Nordic countries in the time period 1964-2003. The increased incidence reflects in part different UV exposure behavior in the population, but hereditary risk factors including skin type are also important. Short intermittent exposure with sunburns appears to be the main risk factor. Other important risk factors include the number of melanocytic nevi and the number of dysplastic melanocytic nevi. Primary cutaneous malignant melanoma is thought to develop in a multi-step process. Precursor lesions, such as dysplastic melanocytic nevi develop into a melanoma in situ stage and further into invasive melanoma and eventually metastatic melanoma. Invasive malignant melanoma is traditionally divided into four principal histopathological subgroups based on the microscopical appearance: superficial spreading melanoma (SSM), nodular malignant melanoma (NMM), lentigo maligna melanoma (LMM) and acral lentiginous melanoma (ALM). Here, we explore the skin cuteneous melanoma proteome using TCGA transcriptomics data and antibody-based protein data. 232 genes are suggested as prognostic based on transcriptomics data from 99 patients; 176 genes are associated with unfavorable prognosis and 56 genes are associated with favorable prognosis. TCGA data analysisIn this metadata study, we used data from TCGA where transcriptomics data was available from 99 patients with skin cutaneous melanoma in total. The total dataset included 40 females and 59 males. Most of the patients (71 patients) were still alive at the time of data collection. The stage distribution was stage i) 2 patients, stage ii) 62 patients, stage iii) 27 patients, stage iv) 3 patients, and 4 patients with missing stage information. Unfavorable prognostic genes in skin cuteneous melanomaFor unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 176 genes associated with an unfavorable prognosis in skin cuteneous melanoma. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed. MCM6 is a gene associated with an unfavorable prognosis in skin cuteneous melanoma. The best separation is achieved by an expression cutoff at 18 TPM which divides the patients into two groups with 0% 3-year survival for patients with high expression versus 63% for patients with low expression, p-value: 6.97e-4. Immunohistochemical staining using an antibody targeting MCM6 (HPA004818) shows a differential expression pattern in skin cuteneous melanoma samples.
p<0.001
TIMELESS is another gene associated with an unfavorable prognosis in skin cuteneous melanoma. The best separation is achieved by an expression cutoff at 17 TPM which divides the patients into two groups with 0% 3-year survival for patients with high expression versus 43% for patients with low expression, p-value: 4.55e-4. Immunohistochemical staining using an antibody targeting TIMELESS (HPA060655) shows a differential expression patterns in skin cuteneous melanoma samples.
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Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in skin cuteneous melanoma.
Favorable prognostic genes in skin cuteneous melanomaFor favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 56 genes associated with a favorable prognosis in skin cuteneous melanoma. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed. NFKB2 is a gene associated with a favorable prognosis in skin cuteneous melanoma. The best separation is achieved by an expression cutoff at 12 TPM which divides the patients into two groups with 45% 3-year survival for patients with high expression versus 0% for patients with low expression, p-value: 5.39e-5. Immunohistochemical staining using an antibody targeting NFKB2 (HPA007493) shows a differential expression pattern in skin cuteneous melanoma samples.
p<0.001
LGALS1 is a gene associated with a favorable prognosis in skin cuteneous melanoma. The best separation is achieved by an expression cutoff at 1623 TPM which divides the patients into two groups with 62% 3-year survival for patients with high expression versus 15% for patients with low expression, p-value: 6.54e-4. Immunohistochemical staining using an antibody targeting LGALS1 (CAB002157) shows a differential expression pattern in skin cuteneous melanoma samples.
p<0.001
Table 2. The 20 genes with highest significance associated with a favorable prognosis in skin cuteneous melanoma.
The skin cuteneous melanoma transcriptomeThe transcriptome analysis shows that 68% (n=13667) of all human genes (n=20162) are expressed in skin cuteneous melanoma. All genes were classified according to the skin cuteneous melanoma-specific expression into one of five different categories, based on the ratio between mRNA levels in skin cuteneous melanoma compared to the mRNA levels in the other 16 analyzed cancer tissues.
Figure 1. The distribution of all genes across the five categories based on transcript abundance in skin cuteneous melanoma as well as in all other cancer tissues. 352 genes show some level of elevated expression in skin cuteneous melanoma compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3. Table 3. The number of genes in the subdivided categories of elevated expression in skin cuteneous melanoma.
Additional informationThe histopathological features of malignant melanomas vary widely. A typical feature, often facilitating the diagnosis of melanoma, is the occurrence of a pagetoid growth pattern, characterized by the growth of melanoma cells in the upper layers of the epidermis from below, as opposed to the localization of normal melanocytes in basal layers of the epidermis. Melanoma cells can be large and rich in cytoplasm, small or even spindly. In a subset of melanomas, there are areas with abundant melanin and in other melanomas, melanin pigment is scarce or absent. Tumor cell nuclei are enlarged, often with a prominent nucleolus and mitoses are present at a variable degree. Patients that present with an advanced tumor stage at the time for diagnosis and patients with relapse of melanoma after surgical removal generally have a poor prognosis. In patients diagnosed with localized disease, the most important prognostic indicator is tumor thickness at the time of diagnosis. The tumor thickness is measured in mm, according to a system initially described by Breslow, and is the dominating parameter for determining the tumor stage (T-stage) of melanoma. Other prognostic factors include mitotic rate and ulceration, as well as clinical factors such as age, gender and the anatomic site of the primary tumor. In Sweden, the 5-year melanoma-specific survival rate is 98% for patients in stage IA (tumor thickness <1mm without ulceration, and 49% for patients in stage IVB (tumor thickness >4 mm with ulceration). Immunohistochemistry is often used to distinguish malignant melanoma from other tumor types. Traditionally, antibodies towards different S-100 proteins have been used as markers of melanocytes, however, these antibodies also stain in e.g. Langerhans cells and nerve fibers. Other markers, such as Melan-A (MART-1) and tyrosinase (TYR), stain melanocytes more specifically and are useful to determine if a tumor is of melanocytic origin. Proliferation markers are also widely used in the differential diagnostics of melanocytic lesions with uncertain malignant potential. The most accepted marker for determining mitotic cells is Ki-67 (MKI67). The presence of Ki-67 positive melanocytic cells is often used in routine pathology to distinguish malignant melanoma from benign melanocytic tumors. Relevant links and publications Uhlen M et al., A pathology atlas of the human cancer transcriptome. Science. (2017) |