Clinicopathologic and molecular characteristics of acral melanomas harboring RARA fusions

Area of Science:

• Oncology
• Genetics
• Dermatology

Background:

• The role of RARA (Retinoic Acid Receptor Alpha) fusions in solid tumors, unlike in hematologic malignancies such as acute promyelocytic leukemia (APL), is largely unexplored.
• Cutaneous melanomas, particularly the acral subtype, present unique clinical and molecular characteristics.

Purpose of the Study:

• To conduct a comprehensive clinicopathologic and molecular analysis of acral melanomas harboring RARA fusions.
• To investigate the potential therapeutic implications of RARA fusions in melanoma.

Main Methods:

• Case study involving two patients with acral melanoma.
• Detailed clinicopathologic examination, including Breslow thickness, ulceration, and mitotic rate.
• Comprehensive molecular profiling, including tumor mutational burden assessment and identification of gene fusions and amplifications.

Main Results:

• Two cases of acral melanoma with RARA fusions were identified in adult patients.
• Molecular analysis revealed low tumor mutational burden and distinct genetic alterations, including a LOC107984974::RARA fusion in one case and RARA::LRP5/RARA::RNF169 fusions with 11q13 amplifications in the other.
• One patient developed brain metastasis, while outcomes for the other varied, with one alive with disease and the other recurrence-free.

Conclusions:

• RARA fusions are identified in acral melanomas, broadening the understanding of their oncogenic role beyond hematologic cancers.
• The genetic landscape of these RARA-fusion-positive melanomas includes low mutational burden and specific amplifications.
• Targeted therapies directed at RARA fusions may hold promise for a subset of melanoma patients, similar to their efficacy in APL.