2012 European Thyroid Association Guidelines for Genetic Testing and Its Clinical Consequences in Medullary Thyroid Cancer

Abstract

Twenty-five percent of medullary thyroid cancers (MTC) are familial and inherited as an autosomal dominant trait. Three different phenotypes can be distinguished: multiple endocrine neoplasia (MEN) types 2A and 2B, in which the MTC is associated with other endocrine neoplasias, and familial MTC (FMTC), which occurs in isolation. The discovery that germline RET oncogene activating mutations are associated with 95–98% of MEN 2/FMTC syndromes and the availability of genotyping to identify mutations in affected patients and their relatives has revolutionized the diagnostic and therapeutic strategies available for the management of these patients. All patients with MTC, both those with a positive familial history and those apparently sporadic, should be submitted to RET genetic screening. Once an RET mutation has been confirmed in an index patient, first-degree relatives should be screened rapidly to identify the 50% who inherited the mutation and are therefore at risk for development of MTC. Relatives in whom no RET mutation is identified can be reassured and discharged from further follow-up, whereas RET-positive subjects (i.e. gene carriers) must be investigated and a therapeutic strategy initiated. These guideline recommendations are derived from the most recent studies identifying phenotype-genotype correlations following the discovery of causative RET gene mutations in MEN 2 eighteen years ago. Three major points will be discussed: (a) identification of patients and relatives who should have genetic screening for RET mutations, (b) management of asymptomatic gene carriers, and (c) ethics.

Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades

“…In our center, we have observed one of the highest percentages of hereditary forms of MTC (30.8%, 58/188) compared with 25% that are globally reported (11). One cannot exclude a bias, as this was the first center performing RET screening in our country.…”

“…The ETA guidelines also recommend genetic screening in all apparently sporadic cases (11). This strategy is expected to increase the probability of identifying new MEN2 kindreds.…”

“…The indications for screening and intervention follow a mutation-based risk classification for MTC patients and carriers according to the guidelines of the American Thyroid Association (ATA) (10) and the European Thyroid Association (ETA) (11). However, the spectrum of mutations is not the same in all ethnic groups.…”

A newly identified missense mutation in <i>RET</i> codon 666 is associated with the development of medullary thyroid carcinoma [Rapid Communication]

“…RET mutation analysis is recommended in all cases of MTC as the mutations are frequently detected in cases of hereditary MTC, such as MEN2A [10]. It is also helpful to predict the disease prognosis because of the disease or when insufficient data are available regarding family members with MEN2 [2,5].…”

Revisão dos casos de MEN 2A numa população pediátrica

“…The Ret tyrosine kinase receptor is expressed in a variety of neuronal cell lineages, including thyroid C-cells and adrenal medulla. 2 The disease phenotype strongly correlates with mutations in specific Ret codons. Genetic testing has become an important tool in the assessment of these patients and in the decision whether to perform prophylactic thyroidectomy.…”