M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds

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Martins-Costa, M. Ceclia ; Cunha, Lucas L. ; Lindsey, Susan C. ; Camacho, Cleber P. ; Dotto, Renata P. ; Furuzawa, Gilberto K. ; Sousa, M. Sharmila A. ; Kasamatsu, Teresa S. ; Kunii, Ilda S. ; Martins, Mrcio M. ; Machado, Alberto L. ; Martins, Joao R. M. ; Dias-da-Silva, Magnus R. ; Maciel, Rui M. B.

• Document type: Journal article
• Source: Endocrine-Related Cancer; v. 23, n. 12, p. 909-920, DEC 2016.
• Web of Science Citations: 8

Abstract

Germline mutations in codon 918 of exon 16 of the RET gene (M918T) are classically associated with multiple endocrine neoplasia type 2B ( MEN 2B) with highly aggressive medullary thyroid cancer (MTC), pheochromocytoma and a unique phenotype. The objectives of this study are to describe the rare M918V RET mutation discovered in 8 MTC kindreds from Brazil lacking the MEN 2B phenotype classically observed in M918T patients and to investigate the presence of a founder effect for this germline mutation. Eight apparently sporadic MTC cases were diagnosed with the germline M918V RET mutation. Subsequently, their relatives underwent clinical and genetic assessment (n = 113), and M918V was found in 42 of them. Until today, 20/50 M918V carriers underwent thyroidectomy and all presented MTC/C-cell hyperplasia; the remainder carriers are on clinical follow-up. None of the M918V carriers presented clinical features of MEN 2B. Their clinical presentation was heterogeneous, and the age at tumor diagnosis ranged from 24 to 59 years. Lymph node metastases were present in 12/20 patients, and presumable distant metastases in 2/20; in contrast, we observed a carrier of up to 87 years of age without evidence of MTC. Ethnographic fieldwork and haplotype analyses suggested that the founder mutation first settled in that area fifteen generations ago and originated from Portugal. Our study is the first to demonstrate the RET M918V mutation co-segregating in 8 familial MTC kindreds with validated evidence of a founder effect. We suggest that M918V MTC should be clinically considered an American Thyroid Association (ATA) moderate-risk category. (AU)

• FAPESP's process: 12/21942-1 - Perceptions and attitudes of patients, relatives, health professionals and regulators on bioethical issues in Brazil and the United Kingdom: the case study of the familial medullary thyroid carcinoma
• Grantee: Maria Sharmila Alina de Sousa
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 06/60402-1 - Medular carcinoma of the thyroid: revisiting the clinical, molecular biological, biochemical and biological aspects following findings of molecular genetics
• Grantee: Rui Monteiro de Barros Maciel
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/06570-6 - Comprehensive whole exome, paired-end RNA and genome sequencing: new insights into genetic bases of thyroid carcinoma in pediatric and adult ages and applications in clinical practice
• Grantee: Janete Maria Cerutti
• Support Opportunities: Research Projects - Thematic Grants