Pathway Alterations in Stage II/III Primary Melanoma

Area of Science:

• Oncology
• Genetics
• Genomics

Background:

• Melanoma genomic classification traditionally focuses on BRAF, NRAS, and NF1 mutations.
• The clinical utility of current genomic classifications is limited, with underexplored alterations in other oncogenic pathways.

Purpose of the Study:

• To examine mutual exclusivity and co-occurrence of genomic alterations across 11 cancer pathways in primary melanomas.
• To identify targetable mutations in early-stage melanoma.

Main Methods:

• Analysis of somatic mutations and copy number alterations in 495 stage II/III primary melanomas from the InterMEL study.
• Utilized next-generation sequencing data from a clinical sequencing panel.

Main Results:

• Mutations in the RTK-RAS pathway were found in 81% of cases, with TP53 (31%) and Cell Cycle (30%) also frequent.
• 81% of cases had at least one targetable mutation; RTK-RAS pathway showed strong mutual exclusivity for BRAF, NRAS, and NF1.
• A higher frequency of RTK-RAS singletons was observed compared to The Cancer Genome Atlas, suggesting early-stage events.

Conclusions:

• RTK-RAS pathway mutations dominate in primary melanomas.
• The identified actionable mutations in well-known pathways suggest potential targeted therapy strategies for early-stage cases.