NF1gene inactivation acts as a tumor driver inRET/RAS-negative medullary thyroid carcinomas

Abstract Objective About 20% of sporadic medullary thyroid carcinomas (MTC) have no RET/RAS somatic alterations or other known gene alterations. The aim of this study was to investigate RET/RAS-negative MTC for the presence of NF1 alterations. Methods We studied 18 sporadic RET/RAS-negative MTC cases. Next-generation sequencing (NGS) of tumoral and blood DNA was performed using a custom panel including the entire coding region of the NF1 gene. The effect of NF1 alterations on the transcripts was characterized by reverse transcriptase–polymerase chain reaction (RT–PCR), and the loss of heterozygosity (LOH) of the other NF1 allele was investigated with Multiplex Ligation-dependent Probe Amplification (MLPA). Results Two cases showed biallelic inactivation of NF1 with a prevalence of about 11% of RET/RAS-negative cases. In a patient affected by neurofibromatosis, there was a somatic intronic point mutation determining the transcript alteration in 1 allele and a germline LOH in the other. In a second patient, we described that both the point mutation and the LOH were 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. Conclusions About 11% of our series of sporadic RET/RAS-negative MTC harbor biallelic inactivation of the NF1 suppressor gene also regardless of neurofibromatosis status. According to our results, NF1 alterations should be searched in all RET/RAS-negative MTC as possible drivers. Moreover, this finding reduces the number of negative sporadic MTC and may have important clinical implications in the management of these tumors.