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Published on: August 25, 2021
NF1 Gene Inactivation Acts as Tumor Driver in RET/RAS Negative Medullary Thyroid Carcinomas
Raffaele Ciampi1, Teresa Ramone1, Cristina Romei1
1Unit of Endocrinology, Department of Clinical and Experimental Medicine, University-Hospital of Pisa, 56124 Pisa, Italy.
Objective:
20% of sporadic MTC has no RET/RAS somatic alterations or other known gene alterations. 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 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 were characterized by RT-PCR and the loss of heterozygosity of the other NF1 allele was investigated with Multiplex Ligation-dependent Probe Amplification.
Results:
Two cases showed bi-allelic 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 one allele and a germline loss of heterozygosity (LOH) in the other. In the other case described 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 NF1 suppressor gene also regardless neurofibromatosis status. According to our results, NF1 alterations should be searched in all RET/RAS negative MTC as possible driver. Moreover, this finding reduces the number of negative sporadic MTCs and may have important clinical implications in the management of these tumors.
Insights
About 11% of sporadic MTC lacking RET/RAS alterations harbor NF1 gene inactivation. This suggests NF1 alterations are a potential driver in these tumors, regardless of neurofibromatosis status.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Sporadic medullary thyroid carcinoma (MTC) often lacks known driver mutations.
- RET/RAS pathway alterations are common in MTC, but a subset remains genetically undefined.
Purpose of the Study:
- To investigate the role of Neurofibromatosis type 1 (NF1) gene alterations in sporadic MTC cases negative for RET/RAS mutations.
- To determine the frequency and mechanism of NF1 inactivation in this MTC subset.
Main Methods:
- Next-generation sequencing (NGS) of tumoral and blood DNA from 18 sporadic RET/RAS-negative MTC cases.
- Analysis of the NF1 gene coding region, transcript alterations via RT-PCR, and loss of heterozygosity (LOH) using Multiplex Ligation-dependent Probe Amplification (MLPA).
Main Results:
- Biallelic inactivation of the NF1 gene was identified in approximately 11% (2 out of 18) of sporadic RET/RAS-negative MTC cases.
- One case involved a somatic mutation and germline LOH, while the other showed both somatic mutation and somatic LOH, indicating NF1's driver role independent of RET/RAS and neurofibromatosis.
Conclusions:
- NF1 gene biallelic inactivation is a significant finding in approximately 11% of sporadic RET/RAS-negative MTC.
- NF1 alterations should be considered as potential drivers in all RET/RAS-negative MTC, irrespective of neurofibromatosis status.
- Identifying NF1 alterations may refine MTC classification and guide clinical management.
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