M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds.
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.
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.|Center for Endocrinology and MetabologyHospital Geral de Fortaleza, Fortaleza, CE, Brazil.|Department of MedicineUniversidade de Fortaleza, Fortaleza, CE, Brazil.
M Cecília
MC
Martins-Costa
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Lucas L
LL
Cunha
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Susan C
SC
Lindsey
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Cleber P
CP
Camacho
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Renata P
RP
Dotto
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Gilberto K
GK
Furuzawa
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
M Sharmila A
MS
Sousa
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Teresa S
TS
Kasamatsu
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Ilda S
IS
Kunii
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Márcio M
MM
Martins
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.|Fleury Medicine and HealthSão Paulo, SP, Brazil.
Alberto L
AL
Machado
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
João R M
JR
Martins
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil rui.maciel@unifesp.br mrdsilva@unifesp.br.
Magnus R
MR
Dias-da-Silva
Department of MedicineThyroid Diseases Center and Laboratory of Molecular and Translational Endocrinology, Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil rui.maciel@unifesp.br mrdsilva@unifesp.br.|Fleury Medicine and HealthSão Paulo, SP, Brazil.
Rui M B
RM
Maciel
D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D001938:Brazil; D018276:Carcinoma, Medullary / Q000151:congenital* / Q000235:genetics; D002648:Child; D005190:Family; D005260:Female; D018703:Founder Effect; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*; D014633:Valine / Q000235:genetics; D055815:Young Adult
D008715:Methionine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D014633:Valine
RET M918V; RET mutation; founder effect; medullary thyroid carcinoma