SOX11, SOX10 and MITF Gene Interaction: A Possible Diagnostic Tool in Malignant Melanoma

Abstract

Malignant melanoma (MM) is a highly heterogenic tumor whose histological diagnosis might be difficult. This study aimed to investigate the diagnostic and prognostic utility of the conventional pan-melanoma cocktail members (HMB-45, melan-A and tyrosinase), in conjunction with SOX10 and SOX11 immunohistochemical (IHC) expression. In 105 consecutive cases of MMs and 44 of naevi, the IHC examination was performed using the five-abovementioned markers, along with microphthalmia transcription factor (MITF), S100, and Ki67. Correlation with the clinicopathological factors and a long-term follow-up was also done. Survival analysis was performed with Kaplan-Meier curves and compared with TCGA public datasets. None of the 44 naevi expressed SOX11, but its positivity was seen in 52 MMs (49.52%), being directly correlated with lymphovascular invasion, the Ki67 index, and SOX10 expression. HMB-45, SOX10, and tyrosinase, but not melan-A, proved to differentiate the naevi from MMs successfully, with high specificity. Triple MITF/SOX10/SOX11 co-expression was seen in 9 out of 15 negative conventional pan-melanoma-cocktail cases. The independent prognostic value was proved for the conventional pan-melanoma cocktail (triple positivity for HMB-45, melan-A, and tyrosinase) and, independently for HMB-45 and tyrosinase, but not for melan-A, SOX10, or SOX11. As consequence, to differentiate MMs from benign naevi, melan-A should be substituted by SOX10 in the conventional cocktail. Although the conventional pan-melanoma cocktail, along with S100 can be used for the identification of melanocytic origin of tumor cells and predicting prognosis of MMs, the conventional-adapted cocktail (triple positivity for HMB-45, SOX10, and tyrosinase) has a slightly higher diagnostic specificity. SOX11 can be added to identify the aggressive MMs with risk for lymphatic dissemination and the presence of circulating tumor cells.

Keywords: MITF; SOX10; SOX11; immunohistochemistry; melanoma cocktail; survival.

Figure A1

The mRNA expression profile across all tumor samples and paired normal tissue generate using Gene Expression Profiling Interactive Analysis project (GEPIA), (A) SOX11, (B) MITF, and (C) SOX10.

Figure 1

Immunohistochemical profile of naevi (left columns) vs. malignant melanomas (right columns), highlighted with Red Magenta Substrate Chromogen. HMB-45 can mark both naevi (A) and melanoma cells (B), same as melan-A (C,D), tyrosinase (E,F), microphthalmia transcription factor (MITF) (G,H) and SOX10 (I,J). No immunoreactivity is observed for SOX11 in naevi (K), but melanomas can present nuclear stain (L).

Figure 2

In skin cutaneous melanomas, the Venn diagram shows interaction between conventional pan-melanoma cocktail (triple positivity for HMB-45/melan-A/tyrosinase), SOX11, SOX10, and MITF.

Figure 3

SOX11 SOX10, and MITF gene interaction generated using miRNET emphasizes direct interaction with miR-101-3p and miR-145-5p. Figure legend: Yellow circle: Gene; green circle: Transcription factor (TF); and blue square: miRNA.

Figure 4

Univariate Kaplan–Meier survival analysis shows independent prognostic value for both (D) conventional pan-melanoma cocktail (triple positivity for HMB-45/melan-A/tyrosinase) and (E) conventional-adapted cocktail (triple positivity for HMB-45/SOX10/tyrosinase) and, independently, for (A) HMB-45 and (C) tyrosinase, but not for (B) melan-A.

Figure 5

In the present cohort (1), univariate Kaplan–Meier survival analysis did not sustain the independent prognostic value of (A) SOX11, (B) SOX10, (C) MITF, or (D) co-expression of SOX11, SOX10, and MITF. In cutaneous melanomas, the TCGA dataset, which was examined using GEPIA (2), also inform the independent prognostic value of these factors (E) SOX11, (F) SOX10 and (H) co-expression of SOX11, SOX10, and MITF, except the (G) MITF gene signature.