An Unexpected Finding of a PTPN11 Germline Mutation in a Patient With a Melanocytic Lesion With a Somatic MAP2K1 Mutation. Coincidence or Not?

Abstract

Melanocytic tumors are a diverse group of lesions and are traditionally classified based on a combination of clinical presentation as well as histological examination. More recently, molecular diagnostics has become an increasingly important part of differentiating different melanocytic lesions in the current WHO standards. This molecular testing, however, can result in unexpected findings. In this report, we describe that molecular testing of a clinical atypical melanocytic lesion showed a mutation in the MAP2K1 gene as well as an unexpected germline mutation in PTPN11, indicative of Noonan syndrome. Based on these findings we concluded that the patient had a MAP2K1 associated melanocytic lesion with Noonan syndrome as an incidental finding. Melanomas are classically not associated with Noonan syndrome. However, we hypothesized that the germline mutations of PTPN11 and the somatic second hit mutation in the MAP2K1 genes might be involved in the formation of the aforementioned lesion. As they are both part of the RAS-MAPK pathway. Furthermore, with the expansion of molecular diagnostics in melanomas, we expect to find an increase in unexpected (germline) mutations.

Keywords: Noonan syndrome; RAS‐MAPK pathway; melanoma; molecular pathology.

FIGURE 1

(A) Histology showing a compound melanocytic lesion with a slightly atypical architecture and many dermal melanophages (H&E). (B) A close‐up view of the lesion, with nests (circle) of mildly atypical melanocytes and some pagetoid spread into the stratum granulosum (arrows). (C) SOX 10 staining highlighting the pagetoid spread of melanocytes. (D) PRAME staining showing overall weak PRAME positivity (25%).

FIGURE 2

Schematic overview of the RAS‐MAPK pathway. The pathway starts by activation of the growth factor (GF) receptor tyrosine kinase (RTK). This phosphorylates a complex of GRB2 and SHP2 (the product of PTPN11 gene), which in turns activates SOS and the rest of the RAS‐MAPK pathway. This in turns affect the transcription of several genes associated with cell proliferation and inhibition of differentiation. This in turn affects the transcription of RNA via methylation processes, regulating proliferation. GRB2, growth factor receptor bound protein 2; SHP2, SRC homology region 2 domain‐containing phosphatase‐2; SOS, son of sevenless; GDP/GTP, G proteins; RAS, rat sarcoma protein; RAF, Ras associated factor; MEK1/2, mitogene‐activated protein kinase kinase (MAP2K); ERK1/2, extracellular signal‐regulated kinase; AP‐1, activating protein 1. Figure made with BioRender.com.