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RET Protooncogene Mutations

The RET (REarranged during Transfection) protooncogene is located on chromosome 10q11.2 and codes for a transmembrane receptor of the tyrosine kinase family. RET gene is expressed in cells derived from the neural crest, the branchial arches, and the urogenital system.

More than 100 mutations, duplications, insertions, or deletions involving RET have been identified in patients with hereditary medullary thyroid carcinoma. Virtually all patients with multiple endocrine neoplasia types 1 and 2 (MEN2A, MEN2B) and familial medullary thyroid cancer (FMTC) have RET germline mutations. Approximately 50% of patients with sporadic medullary thyroid cancer have somatic RET mutations. Sporadic medullary thyroid cancers lacking somatic RET mutations often have somatic mutations of HRAS, KRAS, or rarely NRAS.

Classical MEN2A is the most common MEN2A variant and  95% of patients have RET germline mutations  in codons 609, 611, 618, or 620 of exon 10, or codon 634 of exon 11.  Patients with MEN2B often present with aggressive medullary thyroid cancer during  infancy. Approximately 75% of MEN2B cases are sporadic due to de novo RET mutations. One fourth of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 and less than 5% have RET germline mutations in exon 15.

In new families with hereditary MTC, where the specific RET mutation is unknown, the recommended method of initial testing for MEN2A is to detect RET mutations in exon 10 (codons 609, 611, 618, and 620), exon 11 (codons 630 and 634), and exons 8, 13, 14, 15, and 16. Sequencing of the entire coding region should be reserved for situations where no RET mutation  is identified, or there is a discrepancy between the MEN2 phenotype and the expected genotype.

Patients with the MEN2B phenotype should be tested for the RET codon M918T mutation (exon 16), and if negative, the RET codon A883F mutation (exon 15). If there are no mutations identified in these two exons the entire RET coding region should be sequenced.

Patients with sporadic MTC should have genetic counseling and direct DNA analysis to detect a mutated RET allele. Patients found to have a RET germline mutation should be evaluated, and their first-degree relatives should be offered genetic counseling and genetic testing.

At present there is no indication for evaluating the thyroid tumors of patients with sporadic MTC for the presence of somatic HRAS, KRAS, N RAS, or the RET codon M918T mutation.

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