More than 10% of sporadic RET/RAS-negative medullary thyroid carcinoma (MTC) cases harbor biallelic inactivation of the NF1 gene, a new study published in the European Journal of Endocrinology found. This is regardless of neurofibromatosis status. 

“According to our results, NF1 alterations should be searched in all RET/RAS-negative MTC as possible drivers,” the authors of the study concluded. “Moreover, this finding reduces the number of negative sporadic MTC and may have important clinical implications in the management of these tumors.”

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It is known that in around 20% of sporadic MTC cases, there are no RET/RAS somatic alterations or other known genetic alterations. Here, a team of researchers led by Rossella Elisei, MD, from the Unit of Endocrinology, Department of Clinical and Experimental Medicine, University Hospital of Pisa in Italy studied 18 cases of RET/RAS-negative MTC, looking for the presence of NF1 alterations based on the observation that patients with very advanced disease had a somatic mutation in the NF1 gene.

Of these 18 cases, 2 had biallelic inactivation of NF1. One patient with neurofibromatosis had a somatic intronic point mutation causing transcript alteration in 1 allele and a germline loss of heterozygosity in the other. In the other patient, the point mutation and the loss of heterozygosity were both somatic events. 

“This latter finding shows, for the first time, a driver role of NF1 inactivation in MTC independent of RET/RAS alterations and the presence of neurofibromatosis,” the researchers wrote. “This discovery not only narrows the number of MTC that do not show known genetic alterations but also has a clinical impact on the patients affected by this type of tumor whose current therapeutic options are restricted to targeted therapies.”

MTC is a type of thyroid cancer arising from the parafollicular C cells of the thyroid gland. Around 25% of MTC cases are inherited, and these patients have a mutation in the RET proto-oncogene.

NF1 codes for neurofibromin, which acts as a tumor suppressor protein. Germline alterations in NF1 are responsible for neurofibromatosis type 1, while acquired somatic alterations are associated with the formation of sporadic tumors.


Ciampi R, Ramone T, Romei C, et al. NF1 gene inactivation acts as tumor driver in RET/RAS negative medullary thyroid carcinomas. Eur J Endocrinol. Published online May 22, 2023. doi:10.1093/ejendo/lvad051