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GOPC-ROS1 mosaicism in agminated Spitz naevi: report of two cases
Keisuke Goto1,2,3,4,5, Daniel Pissaloux6,7, Friederike Kauer8
1Department of Pathology, Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, Tokyo, Japan.
Abstract:
Spitz tumors are genetically associated with activating HRAS point mutations or fusions of either ALK, ROS1, NTRK1, NTRK3, RET, MET, MERTK, LCK, BRAF, MAP3K8, or MAP3K3. All these driver gene alterations are mutually exclusive. We report two cases of agminated Spitz naevi with a GOPC-ROS1 fusion. Both cases occurred on the lower limb of young adults. Since adolescence, pigmented or pink-colored papules have been periodically arising in a limited area of skin. In one case, an ill-defined hyperpigmented macule known since childhood was present in the background. Morphologically, at least five lesions were analyzed from each patient. In one case, all were predominantly junctional pigmented Spitz naevi, and in the other case, all were compound unpigmented Spitz naevi. No atypical features were present. RNA-sequencing revealed a GOPC-ROS1 gene translocation in both cases. Split signals of ROS1 gene in fluorescence in situ hybridization were observed not only in the nests of spitzoid melanocytes but also in the bland basal melanocytes surrounding the proliferations. These findings suggest the presence of a GOPC-ROS1 mosaicism in melanocytes with further emergence of agminated Spitz naevi potentially triggered by other genetic alterations. This expands the spectrum of genetic anomalies described in agminated Spitz naevi and our understanding of the mechanisms involved in their emergence.
Insights
Agminated Spitz naevi in young adults were found to harbor a GOPC-ROS1 gene fusion. This genetic anomaly, identified via RNA-sequencing and FISH, suggests melanocyte mosaicism and expands understanding of Spitz tumourigenesis.
Area of Science:
- Dermatopathology
- Cancer Genetics
- Molecular Biology
Background:
- Spitz tumours commonly exhibit activating HRAS mutations or driver gene fusions (e.g., ALK, ROS1).
- These genetic alterations are typically mutually exclusive in Spitzoid neoplasms.
- Agminated Spitz naevi represent a distinct clinical presentation requiring precise molecular characterization.
Purpose of the Study:
- To investigate the genetic underpinnings of agminated Spitz naevi.
- To identify novel gene fusions associated with this specific presentation.
- To explore the potential for melanocyte mosaicism in the development of agminated Spitz naevi.
Main Methods:
- Case study of two young adults with agminated Spitz naevi on the lower limb.
- Morphological analysis of multiple lesions per patient.
- RNA-sequencing to detect gene fusions.
- Fluorescence in situ hybridization (FISH) to confirm gene rearrangements and assess cellular distribution.
Main Results:
- Two cases of agminated Spitz naevi revealed a GOPC-ROS1 gene fusion.
- ROS1 gene rearrangements were detected in both spitzoid melanocytes and surrounding basal melanocytes.
- Lesions presented as pigmented or unpigmented Spitz naevi without atypical features.
Conclusions:
- The GOPC-ROS1 fusion represents a novel genetic alteration in agminated Spitz naevi.
- Findings suggest GOPC-ROS1 mosaicism in melanocytes as a potential mechanism.
- This expands the known spectrum of genetic anomalies in Spitz tumours and informs their pathogenesis.
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