Genetics

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MEN type II is inherited in a classic autosomal dominant mendelian fashion. Initially, using genetic linkage analysis, the genetic defect in FMTC and MEN types IIA and IIB was mapped to the centromeric region of chromosome 10. Subsequent work demonstrated that the RET proto-oncogene was mutated in the vast majority of MEN type II kindreds.67 The RET gene product is a single transmembrane tyrosine kinase-linked receptor (Figure 17-7). The RET protein is expressed by a variety of cells of neural crest origin, including the thyroid C cells and the adrenal medullary cells. This gene product has a large number of cysteine residues in the extracellular domain of the protein. These residues are encoded by exons 10 and 11 of the RET gene. Within this cluster of cysteines, many of the known MEN type IIA and FMTC mutations are found. MEN type IIB is usually caused by a single mutation in the tyrosine kinase domain of the gene, encoded by exon 16 of the RET gene. RET mutations have been found in 97% of MEN type IIA kindreds, 95% of MEN type IIB kindreds, and 88% of those with FMTC.89 Notably, the exon 16 mutation common in MEN type IIB patients has also been identified in approximately 40% of sporadic MTC tumors, where it is assumed to be a somatic, rather than an inherited, mutation in the tumor cells only.10 Within an affected kindred, a single RET mutation is present, and the specific type of mutation is related to the phenotypic expression of the disease within that kindred. The aggressiveness of MTC and the probability of developing pheochromocytoma and parathyroid disease are influenced by the specific RET mutation in a kindred.

In most other hereditary cancer syndromes, the genetic abnormality is a loss-of-function mutation, deletion, or rearrangement in the predisposing gene (eg, MEN type I, von Hippel-Lindau disease, retinoblastoma, and familial polyposis). In contrast, the RET gene is a proto-oncogene rather than a tumor suppressor gene.11 Loss of function of the normal allele has not been demonstrated. Amplification of the mutant allele has been suggested by several recent studies.12 RET gene mutations in the MEN type II syndromes lead to an alteration of function rather than a loss of function. This alteration of function predisposes cells with mutant RET gene-product expression to tumor formation. Given the variable expression of MEN type IIA, it is likely that other genes have an influence on the clinical expression and progression of the disease. Pheochromocytomas from patients with MEN types IIA and IIB have been shown to consistently demonstrate allelic loss of chromosome 1p, but this abnormality is noted infrequently in MTCs.13

RET Proto-Oncogene

RET Proto-Oncogene

Tyrosine kinase

Figure 17-7. Diagram of RET gene product and its mutations in multiple endocrine neoplasia (MEN) type II syndrome. Ovals = locations of germline mutations found in MEN type IIA and familial, non-MEN medullary thyroid carcinoma. Diamonds = location of germline mutations in MEN type IIB. The RET gene product is divided into the intracellular, transmembrane, and extracellular domains. Adapted from Moley JF. Medullary thyroid cancer. In: Clark OH, Duh QY, editors. Textbook of endocrine surgery. Philadelphia: WB Saunders; 1997.

Tyrosine kinase

Figure 17-7. Diagram of RET gene product and its mutations in multiple endocrine neoplasia (MEN) type II syndrome. Ovals = locations of germline mutations found in MEN type IIA and familial, non-MEN medullary thyroid carcinoma. Diamonds = location of germline mutations in MEN type IIB. The RET gene product is divided into the intracellular, transmembrane, and extracellular domains. Adapted from Moley JF. Medullary thyroid cancer. In: Clark OH, Duh QY, editors. Textbook of endocrine surgery. Philadelphia: WB Saunders; 1997.

Prior to the identification of specific RET gene mutations, researchers used linkage analysis to determine if a given patient within a MEN type II kindred had inherited the disease. This technique requires that at least four other family members are affected and is time and effort intensive. Because the mutations that cause the MEN type II syndromes occur in a limited region of the gene and are relatively few, it is now possible to define the specific mutation within almost all affected patients and then screen other family members for that same mutation. This is a much simpler approach. There are no reported cases in which a person from a kindred with a known mutation has had a negative genetic analysis and subsequently developed clinical MEN type II syndrome. Sample mix-ups may occur, however, and must be diligently prevented. Repeat, confirmatory genetic testing is often advisable.

In contrast to MEN type IIA and FMTC, 50% of mutations in MEN type IIB patients arise de novo and cannot be found on genetic screens of the patient's parents. In almost all of these cases, the mutation occured in the patient's paternal allele. In offspring of the patients with de novo mutations, the disease is passed down in a normal autosomal dominant fashion. The rate of de novo cases of MEN type IIA and FMTC is extremely low.

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