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Published on: December 7, 2019
Genomic Fusions in Pigmented Spindle Cell Nevus of Reed
Timothy VandenBoom1, Victor L Quan1, Bin Zhang1
1Department of Dermatology, Feinberg School of Medicine, Northwestern University.
Abstract:
Recent molecular studies of spitzoid neoplasms have identified mutually exclusive kinase fusions involving ROS1, ALK, RET, BRAF, NTRK1, MET, and NTRK3 as early initiating genomic events. Pigmented spindle cell nevus (PSCN) of Reed is a morphologic variant of Spitz and may be very diagnostically challenging, having histologic features concerning for melanoma. Their occurrence in younger patients, lack of association to sun exposure, and rapid early growth phase similar to Spitz nevi suggest fusions may also play a significant role in these lesions. However, to date, there is little data in the literature focused on the molecular characterization of PSCN of Reed with next-generation sequencing. We analyzed a total of 129 melanocytic neoplasms with RNA sequencing including 67 spitzoid neoplasms (10 Spitz nevi, 44 atypical Spitz tumors, 13 spitzoid melanomas) and 23 PSCN of Reed. Although only 2 of 67 (3.0%) of spitzoid lesions had NTRK3 fusions, 13 of 23 (57%) of PSCN of Reed harbored NTRK3 fusions with 5' partners ETV6 (12p13) in 2 cases and MYO5A (15q21) in 11 cases. NTRK3 fusions were confirmed with a fluorescent in situ hybridization break-apart probe. The presence of a NTRK3 fusion correlated with younger age (P=0.021) and adnexal extension (P=0.001). Other minor fusions identified in PSCN of Reed included MYO5A-MERTK (2), MYO5A-ROS1, MYO5A-RET, and ETV6-PITX3 leading to a total of 78% with fusions. Our study suggests that the majority of PSCN of Reed are the result of genomic fusions, and the most frequent and characteristic genomic aberration is an NTRK3 fusion.
Insights
Pigmented spindle cell nevus (PSCN) of Reed, a challenging melanoma mimic, is frequently driven by NTRK3 gene fusions. This molecular finding, identified via next-generation sequencing, distinguishes PSCN of Reed from other spitzoid neoplasms.
Area of Science:
- Dermatopathology
- Molecular Oncology
- Genomics
Background:
- Spitzoid neoplasms, including Pigmented spindle cell nevus (PSCN) of Reed, are challenging to diagnose and can histologically resemble melanoma.
- Kinase fusions (e.g., ROS1, ALK, RET, BRAF, NTRK1, MET, NTRK3) are known early genomic events in spitzoid neoplasms.
- Limited molecular data exists for PSCN of Reed, particularly using next-generation sequencing (NGS).
Purpose of the Study:
- To investigate the molecular landscape of PSCN of Reed using RNA sequencing.
- To identify recurrent genomic alterations, specifically kinase fusions, in PSCN of Reed.
- To compare the molecular profile of PSCN of Reed with other spitzoid neoplasms.
Main Methods:
- RNA sequencing was performed on 129 melanocytic neoplasms, including 67 spitzoid neoplasms and 23 PSCN of Reed.
- Next-generation sequencing identified gene fusions.
- Fluorescent in situ hybridization (FISH) was used to confirm NTRK3 fusions.
Main Results:
- A high frequency of NTRK3 fusions (57%) was observed in PSCN of Reed, with ETV6 or MYO5A as common 5' partners.
- In contrast, only 3.0% of other spitzoid lesions harbored NTRK3 fusions.
- NTRK3 fusions in PSCN of Reed correlated with younger age and adnexal extension. Overall, 78% of PSCN of Reed had detectable fusions.
Conclusions:
- The majority of PSCN of Reed cases are characterized by genomic fusions.
- NTRK3 fusions are the most frequent and characteristic molecular aberration in PSCN of Reed.
- These findings highlight distinct molecular drivers in PSCN of Reed compared to other spitzoid neoplasms.
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