Genetic Abnormalities in Large to Giant Congenital Nevi: Beyond NRAS Mutations

Area of Science:

• Dermatology
• Oncology
• Genetics

Background:

• Large and giant congenital melanocytic nevi (CMN) are rare, often linked to NRAS gene alterations.
• Phenotypic variations within CMN and patient-specific features necessitate deeper molecular investigation.
• Previous studies primarily focused on NRAS and BRAF mutations in single biopsy samples.

Purpose of the Study:

• To comprehensively molecularly characterize a cohort of large/giant CMN, including those with spilus-type nevi.
• To investigate the genetic landscape of different areas within CMN and associated satellite lesions.
• To identify novel molecular drivers beyond common NRAS/BRAF mutations in CMN.

Main Methods:

• Analysis of 53 fresh frozen biopsy samples from 21 large/giant CMN patients using a multigene panel and RNA sequencing.
• Phenotypic characterization of 40 distinct CMN areas and 13 satellite lesions.
• Mutational screening and RNA sequencing to detect point mutations and fusion transcripts.

Main Results:

• Mutations were identified in 76.2% of large/giant CMN cases.
• NRAS mutations were found in 57.1% of patients; other mutations (BRAF, KRAS, APC, MET) in 14.3%.
• Novel fusion transcripts (ZEB2-ALK, SOX5-RAF1) were detected in patients lacking missense mutations, present in distinct affected skin areas.

Conclusions:

• Large/giant CMN pathogenesis involves diverse molecular events, including NRAS mutations, other point mutations, and fusion transcripts.
• The presence of distinct molecular alterations in different CMN areas highlights potential intra-lesional heterogeneity.
• These findings expand the understanding of CMN genetics and suggest new avenues for molecular diagnosis and targeted therapies.