Alternative driver pathways in peripheral nerve sheath tumors – Including DICER1 and/or KRAS alterations Journal Article
| Authors: | Chang, H. Y.; Saoud, C.; Torrence, D.; Tap, W.; Chi, P.; Antonescu, C. R. |
| Article Title: | Alternative driver pathways in peripheral nerve sheath tumors – Including DICER1 and/or KRAS alterations |
| Abstract: | DICER1-associated sarcoma is an emerging entity, defined by either somatic or germline dicer 1, ribonuclease III (DICER1) mutations and sharing characteristic morphologic features irrespective of the site of origin. In addition to the DICER1 driver mutation, concurrent genomic alterations, including tumor protein 53 (TP53) inactivation and RAS pathway activation, are frequently detected. Tumors that morphologically resemble malignant peripheral nerve sheath tumor (MPNST) have rarely been reported among DICER1 sarcomas and often pose diagnostic challenges. This study was prompted by a case involving morphologic features of MPNST, which harbored co-existing DICER1 and hotspot KRAS mutations. Hence, we investigated the incidence of these alterations in PNST from our molecular database compared to the genomic and morphologic spectrum of DICER1-mutant sarcomas. In total, we identified three cases diagnosed as MPNST with co-existing DICER1, ATRX chromatin remodeler (ATRX), and KRAS G12V/A alterations occurring in brain, cerebellopontine angle, and intra-abdominal sites. Two additional cases each of MPNSTs and neurofibromas were identified with hotspot KRAS mutations. All five MPNSTs lacked canonical neurofibromin 1 (NF1)/neurofibromin 2 (NF2) alterations, displaying a classic morphologic appearance with fascicular monomorphic spindle cells and followed a diverse clinical behavior. Among the 38 DICER1-associated sarcomas in our database, eight (21%) had secondary KRAS hotspot mutations, all composed of monomorphic spindle and/or round cells, including three with an MPNST-like histology. In contrast, all 10 (26%) DICER1-mutant sarcomas with TP53 mutations showed a pleomorphic phenotype. The DNA-based methylation profile of our index case clustered within the group of sarcomas with DICER1 alterations. Our results highlight a small subset of MPNST associated with DICER1 and/or KRAS mutations. However, their relationship with conventional MPNST remains to be determined in larger studies. © 2025 The Pathological Society of Great Britain and Ireland. © 2025 The Pathological Society of Great Britain and Ireland. |
| Keywords: | immunohistochemistry; adult; clinical article; controlled study; human tissue; aged; middle aged; primary tumor; unclassified drug; methylation; genetics; mutation; clinical feature; histopathology; cancer recurrence; cisplatin; doxorubicin; gemcitabine; cancer radiotherapy; comparative study; methotrexate; nuclear magnetic resonance imaging; brain tumor; follow up; disease association; protein p16; etoposide; clinical assessment; incidence; epidermal growth factor receptor; cohort analysis; genetic association; pathology; immunoreactivity; data base; retrospective study; dna methylation; distant metastasis; ifosfamide; docetaxel; protein tyrosine kinase inhibitor; sarcoma; dead box protein; dead-box rna helicases; fluorescence in situ hybridization; dna; chromatin; telomerase reverse transcriptase; cytoplasm; neurofibromin; genomics; spindle cell; protein s 100; mitosis rate; retroperitoneal tumor; cyclin dependent kinase inhibitor 2a; kras; molecular biology; hemangiopericytoma; k ras protein; small intestine; protein p21; proto-oncogene proteins p21(ras); malignant peripheral nerve sheath tumor; mpnst; nerve sheath tumor; nerve sheath neoplasms; femur; peripheral nerve sheath tumor; neurofibroma; peripheral nerve; merlin; soft tissue tumor; kras protein, human; cyclin dependent kinase 4; retroperitoneum; ribonuclease iii; crohn disease; parietal lobe; fumarate hydratase; distal femur; cyclin dependent kinase inhibitor 2b; cervical spine; tp53; brain tissue; dna glycosylase muty; dicer1 protein, human; interleukin 7 receptor; atrx; coagulative necrosis; abdominal tumor; hyaline degeneration; retinoblastoma binding protein 2; pons angle; internal auditory canal; transcription factor sox10; hemihypertrophy; epidermal nevus; humans; human; male; female; article; dicer1; neurofibrosarcoma; h3k27me3 protein; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1; transcriptional regulator atrx; rapamycin-insensitive companion of mtor; mouse double minute 2 homolog; anatomical location; dicer1 syndrome; splicing factor 3b subunit 1; satb2 protein; dicer 1 ribonuclease iii; drosha protein |
| Journal Title: | Journal of Pathology |
| Volume: | 265 |
| Issue: | 3 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2025-03-01 |
| Start Page: | 372 |
| End Page: | 384 |
| Language: | English |
| DOI: | 10.1002/path.6391 |
| PUBMED: | 39846292 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Cristina R Antonescu -- Source: Scopus |
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