Recurrent EGFR alterations in NTRK3 fusion negative congenital mesoblastic nephroma

Area of Science:

• Pediatric Pathology
• Molecular Oncology
• Genetics

Background:

• Congenital mesoblastic nephroma (CMN) is a rare infantile tumor.
• The ETV6-NTRK3 fusion is a known driver in a subset of CMN.
• Identifying alternative oncogenic drivers is crucial for CMN classification.

Purpose of the Study:

• To identify oncogenic driver mutations in CMN cases without ETV6-NTRK3 fusions.
• To evaluate the diagnostic utility of these mutations.

Main Methods:

• Retrospective review of CMN cases from institutional databases.
• Exclusion of cases with ETV6 rearrangement or unavailable samples.
• Next-generation sequencing (NGS) for genetic analysis.
• Analysis of both internal and collaborative case series.

Main Results:

• Three of four internal CMN cases showed EGFR kinase domain duplication (KDD).
• Two of three external CMN cases also exhibited EGFR KDD, with one having an EGFR splicing mutation.
• EGFR activation, particularly KDD, is a recurrent finding in CMN lacking NTRK3 fusions.
• EGFR KDD supported the diagnosis of CMN in a retroperitoneal mass of unclear origin.

Conclusions:

• EGFR activation is a common genetic event in CMN without NTRK3 fusions.
• CMN can be molecularly subtyped into NTRK3 fusion-positive, EGFR activation-positive, and other categories.
• These molecular findings enhance the diagnostic framework for CMN.