Gene Expression Profile of Benign, Intermediate, and Malignant Spitz and Spitzoid Melanocytic Lesions

Abstract

Spitz and Spitzoid lesions represent one of the most challenging melanocytic neoplasms in dermatopathology. Nosologic classification has been more recently improved by the discovery of novel molecular drivers, particularly translocations. In the current study, we aimed to use an unbiased approach to explore the gene expression profile of a group of melanocytic Spitz and Spitzoid melanocytic lesions ranging from benign lesions to melanoma, including intermediate lesions such as SPARK nevi and atypical Spitz tumors/melanocytomas. Using unsupervised analysis of gene expression data, we found some distinct hierarchical clusters of lesions, including groups characterized by ALK and NTRK translocations. Few non-ALK translocated tumors demonstrated increased ALK expression, confirmed by immunohistochemistry. Spitz tumors with overlapping features of dysplastic nevi, so-called SPARK nevi, appear to have a common gene expression profile by hierarchical clustering. Finally, weighted gene correlation network analysis identified gene modules variably regulated in subtypes of these cases. Thus, gene expression profiling of Spitz and Spitzoid lesions represents a viable instrument for the characterization of these lesions.

Keywords: RNA-sequencing; Spitz; Spitzoid; melanoma; nevus.

Figure 1

Representative histopathology pictures of selected cases from each category. (A) Compound Spitz nevus; (B) Reed nevus with NTRK-MYO5A translocation; (C) ALK-fusion Spitz nevus (TMP3-ALK); (D) “Spark” nevus; (E) Atypical Spitz tumor; (F) Spitzoid melanoma. Low power images magnification is at 4× and high power images are at 20× magnification.

Figure 2

Hierarchical distance-based clustering of samples using gene expression data with the hclust function in R. Clusters for ALK-translocated tumors, SPARK nevi, and Reed nevi are highlighted in red, purple, and blue, respectively.

Figure 3

WGCNA module eigengene plots are separated by the three sample groupings: SPARK group (1), Reed nevi group (2), and ALK group (3).

Figure 3

WGCNA module eigengene plots are separated by the three sample groupings: SPARK group (1), Reed nevi group (2), and ALK group (3).