Recurrent Epidermal Growth Factor Receptor 2 (ERBB2) Mutations Drive the Pathogenesis of Multifocal Neurofibroma...

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• Peripheral nerve sheath tumors (PNSTs) include neurofibromas and schwannomas.
• Sporadic schwannomatosis is typically associated with NF2 or LZTR1 mutations.
• ERBB2 (Epidermal Growth Factor Receptor 2) mutations have been observed in a subset of PNSTs.

Purpose of the Study:

• To investigate the clinicopathologic features of PNSTs with ERBB2 mutations.
• To determine if ERBB2 mutations are associated with specific neurofibroma subtypes.
• To explore the potential role of ERBB2 mutations in neurofibroma development.

Main Methods:

• Selection of ERBB2-mutant PNST cases from an institutional molecular database.
• Matched tumor-normal targeted DNA sequencing.
• Clinical history, radiologic findings, follow-up, and pathologic features review.
• Germline testing for genetic alterations.

Main Results:

• Identified 5 patients with multifocal PNSTs (neurofibroma variants) harboring ERBB2 kinase domain mutations.
• No germline alterations in NF1, NF2, SMARCB1, LZTR1, or chromosome 22q loss were found.
• Patients exhibited stable disease, with one benefiting from HER2-inhibitor therapy.

Conclusions:

• PNSTs with oncogenic ERBB2 mutations are multifocal neurofibromas, not schwannomas.
• ERBB2 mutations may drive neurofibroma genesis independently of syndromic conditions.
• These findings highlight potential therapeutic strategies targeting ERBB2 in neurofibromas.