Not Only RET but NF1 and Chromosomal Instability Are Seen in Young Patients with Sporadic Medullary Thyroid Carcinoma.

Autor:	Castroneves LA; Endocrinology, Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Mangone FRR; Laboratory of Molecular Genetics, Center for Translational Research in Oncology (LIM-24), Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Lerario AM; Endocrine Oncology, University of Michigan Ann Arbor 48109, USA., da Cunha Mercante AM; Pathology, Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Batista RL; Endocrinology, Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Barros LRC; Laboratory of Molecular Genetics, Center for Translational Research in Oncology (LIM-24), Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Ferreira CV; Thyroid Unit, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil., Farias EC; Endocrinology, Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Vanderlei FAB; Head and Neck Surgery, Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo 05403-010, Brazil., Maia AL; Thyroid Unit, Endocrine Division, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Brazil., Nagai MA; Laboratory of Molecular Genetics, Center for Translational Research in Oncology (LIM-24), Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil., Jorge AAL; Genetic Endocrinology Unit, Cellular and Molecular Endocrinology Laboratory (LIM-25) Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brazil., Hoff AO; Endocrinology, Instituto do Câncer do Estado de São Paulo, São Paulo 01252-000, Brazil.
Jazyk:	angličtina
Zdroj:	Journal of the Endocrine Society [J Endocr Soc] 2024 Mar 30; Vol. 8 (6), pp. bvae059. Date of Electronic Publication: 2024 Mar 30 (Print Publication: 2024).
DOI:	10.1210/jendso/bvae059
Abstrakt:	Context: Genetic analysis of sporadic medullary thyroid carcinoma (MTC) has revealed somatic variants in RET , RAS , and occasionally other genes. However, around 20% of patients with sporadic MTC lack a known genetic driver. Objective: To uncover potential new somatic or germline drivers, we analyze a distinct cohort of patients with sporadic, very early-onset, and aggressive MTC. Methods: Germline and somatic DNA exome sequencing was performed in 19 patients, previously tested negative for germline RET variants. Results: Exome sequencing of 19 germline samples confirmed the absence of RET and identified an NF1 pathogenic variant in 1 patient. Somatic sequencing was successful in 15 tumors revealing RET variants in 80%, predominantly p.Met918Thr, which was associated with disease aggressiveness. In RET -negative tumors, pathogenic variants were found in HRAS and NF1 . The NF1 germline and somatic variants were observed in a patient without a prior clinical diagnosis of neurofibromatosis type 1, demonstrating that the loss of heterozygosity of NF1 functions as a potential MTC driver. Somatic copy number alterations analysis revealed chromosomal alterations in 53.3% of tumors, predominantly in RET -positive cases, with losses in chromosomes 9 and 22 being the most prevalent. Conclusion: This study reveals that within a cohort of early-onset nonhereditary MTC, RET remains the major driver gene. In RET -negative tumors, NF1 and RAS are drivers of sporadic MTC. In addition, in young patients without a RET germline mutation, a careful clinical evaluation with a consideration of germline NF1 gene analysis is ideal to exclude Neurofibromatosis type 1 (NF1). (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu