Brown Tumors Belong to the Spectrum of KRAS -driven Neoplasms.

Brown tumors are rare and generally self-limiting mass lesions of bone occurring in the context of hyperparathyroidism. Although commonly regarded as endocrine-driven tumor-like lesions, we detected pathogenic hotspot KRAS mutations in 10/16 brown tumors (62%) with similar frequencies found in cases affecting the peripheral and axial skeleton. Pathogenic mutations in other driver genes of the RAS-MAPK pathway were not identified. Our findings suggest brown tumors to represent true neoplasms driven by the activation of the RAS-MAPK signaling pathway. The frequent regression of brown tumors after normalization of hyperparathyroidism points to a second hit mediated by endocrine stimulation to be required for tumor development. Our findings underline the pathogenic relation of brown tumors to nonossifying fibroma and giant cell granuloma of the jaws which both appear histologically similar to brown tumors and are also driven by RAS-MAPK signaling pathway activation.
Competing Interests: Conflicts of Interest and Source of Funding: D.T., S.H., B.A., and D.B. were supported by the Swiss National Science Foundation, the Foundation of the Bone Tumor Reference Centre, the Gertrude von Meissner Stiftung and the Stiftung für krebskranke Kinder, Regio Basiliensis. A.M.F. is supported by the National Institute for Health Research, the Cancer Research UK University College London Experimental Cancer Medicine Centre, the RNOH Research and Development Department and the RNOH Biobank Team and the Tom Prince Trust. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.
(Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)