Characterization of driver oncogenic mutations of in-transit melanoma metastases.

Abstract

9586 Background: In-transit melanoma (ITM) is a distinctive form of melanoma metastasis, marked by aggressive locoregional progression and characterized by the entrapment of tumor cells within the lymphatic channels before reaching regional lymph nodes (LN). The mechanisms leading to lymphatic trapping rather than progression to distant metastasis are not well-understood. Previous research indicates a clonal origin for ITM, suggesting specific early-stage genetic alterations may drive this clinical phenotype. In this study, we sought to identify driver oncogenic mutations specific to ITM that may serve as potential targets. Methods: We analyzed data from the MSK-IMPACT database, which includes targeted sequencing of 341-468 genes for patients with cutaneous melanoma. Patients were stratified into four groups based on the type of sample sequenced: in-transit, primary tumor, regional LN, and distant metastases. We examined the prevalence of driver mutations and genetic variants across these groups, adjusting for multiple comparisons. Results: A total of 528 patients were included, of which 74 were in the ITM, 103 in the primary, 133 in the regional LN, and 218 in the metastatic group. The mean age of the cohort was 59 years (SD = 16) and 67% were male. Among the in-transit samples, 68% were treatment-naïve at the time of sequencing, 36% received anti-PD1 monotherapy, and 12% received anti-PD-1 combination therapy. None of the patients received targeted therapy. NRAS Q61 driver mutations were significantly more common in ITM than all other groups (all p<0.05). NF-1 driver mutations were significantly less common in ITM than distant metastasis (p=0.007) (Table). Comparative analysis across all genes showed a lower incidence of NF-1 mutations in ITM relative to metastatic samples (12% vs 38%, p=0.007). Gene interaction analysis showed mutual exclusivity between NRAS and PAK5 mutations in ITM (p=0.02), but not in other groups (p>0.05). Conclusions: This study reveals distinct driver oncogenic mutations specific to ITM, characterized by a high incidence of NRAS mutations, retained NF-1 function and the novel finding of mutual exclusivity between NRAS and PAK5. Closer examination of the interplay between NRAS, NF-1 and PAK5 interactions in ITM may provide deeper insights into the molecular mechanisms of ITM and offer potential therapeutic targets for ITM. [Table: see text]