Molecular Characterization of Multifocal Granular Cell Tumors

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Granular cell tumors (GrCT) are recently identified to be driven by inactivating mutations in vacuolar H+-ATPase (V-ATPase) genes, particularly ATP6AP1 and ATP6AP2.
• Multifocal GrCT occur in approximately 10% of patients, but the molecular relationship between these distinct tumor sites within a single patient remains unclear.

Purpose of the Study:

• To investigate the molecular distinctions between multifocal granular cell tumors within individual patients.
• To determine if paired primary and metastatic malignant GrCT share identical genetic mutations.

Main Methods:

• Targeted next-generation sequencing of V-ATPase genes was performed on multifocal GrCT samples.
• Whole exome and Sanger sequencing were utilized for paired primary and metastatic malignant GrCT.
• Genetic analysis was conducted on 43 tumors from 13 patients with multiple GrCT.

Main Results:

• Somatic mutations in V-ATPase genes were identified in 76% (32/42) of sequenced tumors.
• Mutations in ATP6AP1 were found in 48% of tumors, ATP6AP2 in 24%, and ATP6V0A4 in 5%.
• Mutually exclusive mutations were observed in at least two tumors within 8 patients, indicating molecular distinctness.

Conclusions:

• Multifocal granular cell tumors within an individual patient are molecularly distinct.
• Paired primary and metastatic malignant granular cell tumors share identical mutations, supporting a common clonal origin.