Alternative driver pathways in peripheral nerve sheath tumors - including DICER1 and/or KRAS alterations

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• DICER1-associated sarcomas are an emerging group of tumors characterized by DICER1 mutations.
• Concurrent genetic alterations like TP53 inactivation and RAS pathway activation are common in these sarcomas.
• Tumors resembling malignant peripheral nerve sheath tumors (MPNSTs) are rarely reported in DICER1 sarcomas and present diagnostic challenges.

Purpose of the Study:

• To investigate the incidence of DICER1 and KRAS mutations in MPNSTs.
• To compare the genomic and morphologic features of MPNSTs with DICER1-mutant sarcomas.
• To characterize a specific subset of MPNSTs associated with DICER1 and/or KRAS alterations.

Main Methods:

• Analysis of a molecular database for DICER1, KRAS, ATRX, TP53, NF1, and NF2 alterations in MPNSTs and DICER1-mutant sarcomas.
• Morphologic evaluation of tumor samples.
• DNA-based methylation profiling.

Main Results:

• Three cases of MPNST with co-existing DICER1, ATRX, and KRAS G12V/A alterations were identified.
• Eight of 38 (21%) DICER1-associated sarcomas harbored secondary KRAS hotspot mutations, with three showing MPNST-like histology.
• DICER1-mutant sarcomas with TP53 mutations (10/38, 26%) displayed a pleomorphic phenotype, contrasting with the monomorphic cells in KRAS-mutated sarcomas.

Conclusions:

• A distinct subset of MPNSTs associated with DICER1 and/or KRAS mutations exists.
• These MPNSTs lack canonical NF1/NF2 alterations and exhibit monomorphic spindle cell morphology.
• Further research is needed to clarify the relationship between these MPNSTs and conventional MPNSTs.