Pathogenesis

The patterns of organ involvement and familial clustering of the MEN syndromes suggest an autosomal dominant mode of inherited transmission in each, with essentially complete penetrance but a varying degree of expression.

In the 1960s, the observation that both thyroid parafollicular C cells (the cells of origin of medullary thyroid carcinoma) and cells of the adrenal medulla (which give rise to pheochromocytomas) derive from the embryonic neural crest and are of the amine precursor uptake and decarboxylation (APUD) variety of neuroendocrine cells led to speculation that a single defect in development of tissues of this origin and nature might underlie the disease. Although attractive at first glance, this hypothesis was understood to be oversimplified in that it failed to adequately account for both the clinicopathologic differences between the MEN syndromes and, in particular, the derangements found in these diseases among cells not possessing APUD characteristics and tissues not derived from the neural crest (e.g., the parathyroid hyperplasia of MEN 2A). Nevertheless, the two syndromes were clearly variations on a common theme of genetic endocrine derangement.

In the late 1980s, several DNA concordance studies definitively mapped the inherited defects of the MEN 2 syndromes (as well as a familial variant of medullary thyroid carcinoma) to the pericentromeric region of chromosome 10.1213 Further work in the early 1990s making use of the advancing DNA technology has shed considerable light on the specific genetic alterations underlying the different phenotypes of these related but distinct diseases.

The ret protooncogene is a segment of the human genome on chromosome 10 that encodes a specific cell surface receptor complex. This receptor, homologous to the well-characterized epidermal growth factor receptor, possesses a large extracellular domain, a single membrane-spanning segment, and an intracellular tyrosine kinase domain putatively involved in signal transduction. Receptors of this kind are believed to play a significant role in the regulation of cell growth and differentiation. The specific ligand and physiologic function of this receptor are, however, unknown. It has been demonstrated that mutations in the segment of the ret proto-oncogene coding for the extracellular domain of the receptor protein are responsible for producing the MEN 2A phenotype as well as sporadic and familial cases of medullary thyroid carcinoma. Studies by Hofstra,14 Carlson,15 and their colleagues, in which they used single-strand polymorphism analysis to examine the DNA from MEN 2B patients, have clearly shown that a single point mutation in the segment of ret encoding the intracellular tyrosine kinase catalytic domain of the protein product is responsible for MEN 2B (Figs. 83-1 and 83-2). This mutation, which alters ret codon 918 from ATG to ACG and thus results in a substitution of threonine for methionine in the receptor catalytic segment, was found in both inherited and sporadic cases of the syndrome. In addition, the mutation was noted in the genetic material of all MEN 2B patients examined. It remains for further study to elucidate the mechanism by which this specific mutation affects ligand binding or, more likely, signal transduction to produce the MEN 2B phenotype. Recent studies have characterized gene expression induced by RET with MEN 2A or 2B mutation. Watanabe and

GK-7

GATC

GATC

GATC

y ATG

N= GTT AAA TGG ATG GCA ATT Val Lys Trp Met Ala lie 918

M= GTT AAA TGG ACG GCA ATT Thr

FIGURE 83-1. The point mutation in the tyrosine kinase domain ret protooncogene, which gives rise to the multiple endocrine neoplasia (MEN) 2B phenotype. DNA sequence analysis of polymerase chain reaction amplification products from genomic DNA of unaffected parents (unshaded square and circle) and daughter with MEN 2B (half-shaded circle) from family-coded GK-7. DNA and corresponding amino acid sequences appear beneath the sequencing ladders. Both parents possess the normal sequence (ATG coding for methionine) for each allele, whereas the daughter has one normal and mutant allele, the mutation being a C for a T substitution at position 918 (asterisk). This produces the codon ACG, which replaces methionine with threonine. (From Carlson K, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the ret proto-oncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Sci U S A 1994;91:1579.)

coworkers identified 10 genes induced by RET-MEN 2 or RET-MEN 2B mutant proteins.16 The inducible genes included cyclin Dl, cathepsins B and L, and coflin—all known to be involved with cell growth tumor progression and invasion. The repressed genes included type I collagen, lysyl oxidase, annexin I, and tissue inhibitor of matrix metallopro-teinase 3—all known to be implicated in tumor suppression. The fact that MEN 2A and 2B arise from separate mutations affecting different domains of a single receptor may also help explain the observed similarities and differences between these entities. Moreover, the observation that the ret protooncogene is expressed in the progenitors of parathyroid cells may provide an explanation for the alterations found in the MEN 2A phenotype among these cells, which are neither of the APUD type nor derived from the neural crest.

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