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

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

Author Martins-Costa, Maria Cecilia Autor UNIFESP Google Scholar
Cunha, Lucas Leite Autor UNIFESP Google Scholar
Lindsey, Susan Chow Autor UNIFESP Google Scholar
Camacho, Cléber Pinto Autor UNIFESP Google Scholar
Dotto, Renata Pires Autor UNIFESP Google Scholar
Furuzawa, Gilberto Koiti Autor UNIFESP Google Scholar
Sousa, Maria Sharmila Alina de Autor UNIFESP Google Scholar
Kasamatsu, Teresa Sayoko Autor UNIFESP Google Scholar
Kunii, Ilda Sizue Autor UNIFESP Google Scholar
Martins, Marcio Maciel Autor UNIFESP Google Scholar
Machado, Alberto L. Autor UNIFESP Google Scholar
Martins, João Roberto Maciel Autor UNIFESP Google Scholar
Dias-da-Silva, Magnus Régios Autor UNIFESP Google Scholar
Maciel, Rui Monteiro de Barros Autor UNIFESP Google Scholar
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.
Keywords medullary thyroid
RET mutation
founder effect
xmlui.dri2xhtml.METS-1.0.item-coverage Bristol
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Fleury Group Research Grant
Grant number FAPESP: 2006/60402-1
FAPESP: 2010/51547-1
FAPESP: 2014/06570-6
FAPESP: 2009/50575-4
FAPESP: 2010/51546-5
FAPESP: 2012/21942-1
Fleury Group Research Grant: 12518
Date 2016
Published in Endocrine-Related Cancer. Bristol, v. 23, n. 12, p. 909-920, 2016.
ISSN 1351-0088 (Sherpa/Romeo, impact factor)
Publisher Bioscientifica Ltd
Extent 909-920
Origin http://dx.doi.org/10.1530/ERC-16-0141
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000388940100015
URI https://repositorio.unifesp.br/handle/11600/56652

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