A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives.

OBJECTIVE: Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision-making. DESIGN AND PATIENTS: We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers. MEASUREMENT AND RESULTS: The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0·7-2·8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma. CONCLUSIONS: A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description.

Evidence for the founder effect of RET533 as the common Greek and Brazilian ancestor spreading multiple endocrine neoplasia 2A.

OBJECTIVES: About one-quarter of patients with medullary thyroid cancer (MTC) have inherited disease due to mutations in the RET gene. A rare mutation in exon 8 (G533C) of RET, previously described in a large Brazilian family with MEN2A, also appeared to be clustering in Greece, whereas it was rarely reported in other ethnic groups. The aim of this study was to identify a possible common ancestry between these carriers. PATIENTS AND METHODS: Twelve RET G533C mutation carriers, four randomly selected from the Brazilian cohort and eight from apparently unrelated Greek families, were studied for a possible common ancestral origin. RET flanking microsatellite markers at chromosome 10q (D10S197, D10S196, D10S1652 and D10S537) were used. RESULTS: Genomic DNA analysis using these markers showed that many of these apparently unrelated individuals shared a common haplotype indicating a common ancestral origin. CONCLUSION: Our data suggest that Brazilian and Greek patients with MTC carrying the G533C mutation in exon 8 of RET gene originate from a common ancestor. Due to historical reasons, we speculate that the more plausible explanation for the origin of this mutation is in Greece.

Genome-wide copy number analysis in a family with p.G533C RET mutation and medullary thyroid carcinoma identified regions potentially associated with a higher predisposition to lymph node metastasis.

CONTEXT: Our group described a p.G533C RET gene mutation in a large family with multiple endocrine neoplasia type 2 syndrome. Clinical heterogeneity, primarily associated with the presence of lymph node metastases, was observed among the p.G533C carriers. OBJECTIVE: The aim of this study was to use single-nucleotide polymorphism-array technology to identify copy number variations (CNVs), which are present in the constitutional DNA and associated with the established clinical and pathological features of aggressive medullary thyroid carcinoma (MTC), primarily the presence of lymph node metastasis. DESIGN: Fifteen p.G533C carriers with MTC were chosen for the initial screening. The subjects were divided into two groups according the presence (n = 8) or absence (n = 7) of lymph node metastasis. Peripheral blood DNA was independently hybridized using a genome-wide single-nucleotide polymorphism Array 6.0 platform. The results were analyzed using both Genotyping Console and PennCNV software. To identify the possible candidate regions associated with the presence of lymph node metastasis, cases (metastatic MTC) were compared with controls (nonmetastatic MTC). The identified CNVs were validated by quantitative PCR in an extended cohort (n = 32). RESULTS: Using two different algorithms, we identified nine CNV regions that may contribute to susceptibility to lymph node metastasis. The validation step confirmed that a CNV loss impacting the FMN2 gene was potentially associated with a greater predisposition to lymph node metastasis in this family (P = .0179). Finally, we sought to investigate whether the development of lymph node metastasis might not depend on a single CNV but rather a combination of various CNVs. These analyses defined a CNV pattern related to a more aggressive phenotype in this family, with CNV deletions being enriched in the metastatic group (P = .0057). CONCLUSION: Although hereditable specific RET mutations are important to determine cancer risk, germline CNVs in disease-affected individuals may predispose them to MTC aggressiveness.