Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer with incompletely understood molecular drivers.
• Merkel cell polyomavirus (MCV) is implicated in 55-90% of MCC cases, but non-viral etiologies also exist.

Purpose of the Study:

• To investigate the molecular pathogenesis of MCC by identifying somatic mutations and functional biomarkers.
• To compare viral (MCV-positive) and non-viral (MCV-negative) MCC etiologies.
• To identify potential therapeutic targets common to both MCC subtypes.

Main Methods:

• Whole-exome sequencing was employed to detect somatic mutations in clinically characterized MCC cases.
• Functional biomarkers reflecting mutated pathway activity were analyzed.
• Multivariable analysis was used to assess survival factors.

Main Results:

• MCV-negative MCC tumors exhibited higher mutational loads with UV signatures and more frequent TP53 and RB mutations compared to MCV-positive tumors.
• Both MCV-positive and MCV-negative MCCs showed nuclear accumulation of oncogenic transcription factors, including nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3.
• Phosphorylated CRE-binding protein (P-CREB) was identified as an independent survival factor.

Conclusions:

• Despite genetic differences, common deregulated pathogenic mechanisms involving NFAT, P-CREB, and P-STAT3 exist in MCC, offering potential therapeutic targets.
• P-CREB is a significant independent prognostic biomarker for MCC patient survival.