Genomic Alterations and Tumor Mutation Burden in Merkel Cell Carcinoma

Area of Science:

• Oncology
• Genomics
• Medical Informatics

Background:

• Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with rising incidence.
• Current treatments like chemotherapy and checkpoint inhibitors are used for metastatic disease, but targeted therapies lack approval.
• Identifying actionable genetic alterations is crucial for developing new treatment strategies.

Purpose of the Study:

• To identify actionable genetic alterations in MCC.
• To correlate these alterations with tumor mutational burden (TMB).
• To assess the therapeutic evidence level of these alterations using the OncoKB database.

Main Methods:

• Retrospective analysis of 324 MCC tumor samples from the AACR GENIE database (2017-2022).
• Utilized next-generation sequencing data to identify genetic alterations.
• Assessed tumor mutational burden (TMB) and OncoKB therapeutic evidence levels (3B and 4).

Main Results:

• 26.2% of MCC cases had high TMB (≥10 mutations/Mb).
• 17.6% of patients had OncoKB level 3B alterations and 8.6% had level 4 alterations.
• Actionable alterations were more frequent in high TMB cases (45.1%) compared to low TMB cases (7.8%).
• Commonly altered pathways included RTK-RAS, TP53, cell cycle, PI3K, and NOTCH.

Conclusions:

• A minority of MCC patients possess potentially actionable genetic alterations.
• These findings support further investigation into targeted therapies for MCC.
• Targeted therapies may be effective as single agents or in combination with immunotherapy or chemotherapy for specific MCC patient groups.