ETA2024 Poster Presentations Anaplastic thyroid cancer (10 abstracts)
NF1 mutations in anaplastic thyroid cancer: from genetic insights to therapeutic potential
Teresa Ramone 1 , Raffaele Ciampi 2 , Loredana Lorusso 3 , Laura Agate 4 , Valeria Bottici 5 , Sandra Brogioni 6 , Eleonora Molinaro 7 , Roberta Casalini 8 , Cristina Romei 9 , Liborio Torregrossa 10 , Clara Ugolini 11 & Rossella Elisei 12
1Endocrinology Unit, Pisa, Italy, Department of Clinical and Experimental Medicina, Endocrinology Unit, University of Pisa; University of Pisa; Department of Clinical and Experimental Medicine, Pisa, Italy; 2Uo Endocrinologia - Ospedale di CISA, Dipartimento di Medicina Clinica e S, Pisa, Italy; 3Thyroid Oncology, University of Pisa, 1. Department of Clinical and Experimental Medicine, Unit of Endocrinology, Pisa University Hospital, Via Paradisa 2, 56124, Pisa, Italy., Thyroid Oncology, University of Pisa, Pisa, Italy; 4University Hospital, 1department of Clinical and Experimental Medicine, Endocrinology Unit, University of Pisa, Italy, Department of Endocrinology, Pisa, Italy; 5University of Pisa, Department of Clinical and Experimental Medicine, Endocrine Unit, Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Pisa, Italy, Pisa, Italy; 6Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Pisa, Italy; 7University of Pisa, Endocrinology Unit, Department of Endocrinology, Pisa, Italy; 8, University of Pisa, Endocrine Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, Department of Clinical and Experimental Medicine, Pisa, Italy; 9Direzione Area di Medicina, University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy; 10Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, University of Pisa and University Hospital of Pisa, Pathology Unit, Pisa, Italy; 11University of Pisa, Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy, Department of Surgical, Medical, Molecular Pathology and Critical Area, Pisa, Italy; 12University of Pisa, Endocrinology Unit, Department of Clinical and Experimental Medicine, Pisa, Italy
Objective: NF1 alterations may be present in about 3% of Anaplastic thyroid cancers (ATC) in alternative to classic driver mutations; moreover, NF1 is included in several trials as target for therapy with MEK inhibitors. The objective of this study is to better characterize the role of NF1 in ATC.
Methods: For this purpose, DNA and RNA were extracted from 32 cases of ATC/PDTC. We firstly analyzed classic driver mutations with 2 Next-Generation Sequencing (NGS) custom panels able to detect mutations/indels and gene fusions. Cases negative from this analysis were analyzed with another panel spanning the entire NF1 tumor suppressor gene. Finally, TERT promoter mutations (C228T, C250T) were investigated as well using droplet digital PCR (ddPCR).
Results: Of the 32 patients analyzed, 7 cases (21.9%) showed driver mutations in BRAF (V600E and K601E), and 5 for RAS (1 HRAS Q61R, 1 HRAS G12R, 2 NRAS Q61K, 1 NRAS G13R+TP53). Other 15 cases were negative for driver mutations but showed different TP53 pathogenic variants (15/32, 46.9%) while the remaining 10 cases (10/32, 31.2%) were negative. TERT C228T mutation was detected in 15/32 (46.9%) cases. Subsequently, 15/25 negative cases were analysed for NF1 gene mutations and in 2 cases (2/15, 13.3%) we found pathogenic variants. In details, in a patient affected by simultaneous ATC and a micro-papillary thyroid carcinoma (mPTC) we found a NF1 pathogenic mutation affecting the donor splicing site upstream exon 39 in the ATC component; the same patient harbored a BRAF V600E mutation in the mPTC component. Interestingly, the 2 mutations were not shared within the 2 lesions. Analysis of the NF1 transcript of the ATC component demonstrated the actual skipping of exon 39. In the second patient, we detected a deletion of two nucleotides in NF1 exon 49 resulting in a frameshift of the coding region and the introduction of a stop codon. Interestingly, in both ATC cases, we found co-occurrent TP53 pathogenic mutations. Since both genes, NF1 and TP53, are located on the chromosome 17 we can hypothesize a synergic role of inactivation of these two tumor suppressor genes in the same lesion.
Conclusions: These data show that NF1 can occur in negative ATC and can act in occurrence with TP53. Since NF1 is used for targeted therapy in other types of cancer, its presence may offer an additional therapeutic option to these patients.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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