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

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.

p.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy

“…Founder mutation and confined geographical clustering for specific RET mutation have been already described; Martins‐Costa et al () demonstrated the presence of a founder effect for Met918Val mutation in Brazil, also in this study haplotype analysis of the founder effect confirmed ethnographic data collected into historical archives of the region (churches’ archives and oral life history narratives). Also for the Gly533Cys mutation described in a large Brazilian family and in Greece, and rarely reported in other ethnic groups, Cunha et al () identified the presence of a common ancestor.…”

Geographic epidemiology of medullary thyroid cancer families: unearthing European ancestral heritage

“…• A p.M918V ancestor from Portugal (city of Braga) who migrated to Northeastern Brazil (state of Ceará) in the 1600s (Martins-Costa et al 2016); • A p.G533C ancestor from Spain (Catalunia region) who migrated to Southeastern Brazil in the late 1800s (Cunha et al 2017).…”

A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals

“…Based on the clinical evaluation and RET genetic screening results, we identified 29 index patients with hereditary MTC and 31 index patients with sporadic MTC (Figure 1). The most frequent mutations found were p.V804L and p.M918V ( (8). We identified only one patient with MEN 2B, who had the classical p.M918V mutation.…”

“…This finding led us to question whether a founder effect could explain the high frequency of the p.M918V mutation in Ceará, as at that time, 8 families with a p.M918V mutation had already been identified. The evidence suggestive of a founder effect as an explanation for the frequency of the p.M918V mutation in Ceará led us to consider whether the first 8 families diagnosed with a p.M918V mutation were actually one large family (8).…”