Mutations involving TGFB and MAPK may be associated with malignancy in granular cell tumors

Abstract

Granular cell tumors are mesenchymal neoplasms of presumed schwannian differentiation that may present as solitary or multifocal lesions with excision usually being curative. A minority of cases, however, shows histological features associated with an increased risk for metastasis and are highly aggressive leading to death in about a third of cases 1 . While benign and malignant cases have been shown to harbor mutations in the H + ATPase genes, there is only limited data examining molecular aberrations associated with malignancy. The departmental archives were searched for cases of atypical/malignant granular cell tumor. Clinical and histopathological features were noted. Whole exome sequencing was performed. Three cases of malignant granular cell tumor and on atypical granular cell tumor were included. Three tumors metastasized to distant sites with a median disease-free survival of 16 months and an overall follow-up time of 32.5 months. Whole exome sequencing showed mutations involving TGFβ and MAPK pathways in all four tumors. Mutations involving the TGFβ and MAPK pathways may be associated with tumor progression or malignant transformation in granular cell tumor pathogenesis.

Utility of sequencing for ATP6AP1 and ATP6AP2 to distinguish between atypical granular cell tumor with junctional component and melanoma

“…For this reason, there has been interest in using NGS to help make these distinctions, with mutations identified in TGFB and MAPK pathways in malignant GCT. 24 We did not identify any recurrent DNA changes distinguishing atypical GCT from the benign variant in our cases. It might be feasible to distinguish these entities based on RNA expression but currently, there are insufficient data.…”

“…In addition, there are reports of benign‐appearing GCTs with metastasis. For this reason, there has been interest in using NGS to help make these distinctions, with mutations identified in TGFB and MAPK pathways in malignant GCT 24 . We did not identify any recurrent DNA changes distinguishing atypical GCT from the benign variant in our cases.…”

Antiangiogenics in Malignant Granular Cell Tumors: Review of the Literature

“…Both pathways are known to play essential roles in the regulation of the cell cycle, tumor formation, and metastasis of many cancers. While they usually operate in opposing roles, with TGFβ-suppressing cell proliferation and MAPK-promoting proliferation, in the event of malignant transformation, both seem to support each other and promote growth and metastasis with TGFβ switching from tumor suppressor to a pro-metastatic factor [34].…”

“…Further investigation into the pathogenesis of this sarcoma subtype continues. Alterations in the MAPK [46,51], PI3K [46], TGFβ [34] pathways, and the description of VATPase [7,8] variants are considered promising therapeutic targets that may provide novelties in the near future. At the same time, immunotherapy is a field that has not yet been explored and, as we previously mentioned, we have preclinical elements that would support research in this area [60,61].…”