The Molecular Biology of MEN

The gene responsible for MEN 1 was identified in 199729 and is located on chromosome 1 lql3. MEN I spans 9 kb of genomic DNA and consists of 10 exons containing an 1830-base pair coding region. MEN I encodes a 610-amino acid nuclear protein, referred to as menin.4'29'32 Menin is localized to the nucleus and interacts with the activating protein 1 transcription factor JunD and other proteins involved in transcription and cell growth regulation.33"35 MEN1 mutations are spread over the entire coding region (exons 2 to 10); approximately 50% are frameshift, 24% are missense, 20% are nonsense, and 7% are deletion or in-frame insertion mutations.36 MEN1 acts as a tumor suppressor gene, and tumor development follows Knudson's "two-hit" hypothesis.37 Hence, individuals affected with MEN 1 inherit one MEN1

TABLE 76-1. MEN 1—Clinical Manifestations*

Manifestations

Prevalence (%)

Major ("3 Ps")

Primary hyperparathyroidism

>95

Pancreatic/duodenal neuroendocrine

50-75

tumors

Pituitary tumors

30-55

Less Common

Adrenocortical tumors (functioning

and nonfunctioning; benign and

malignant)

Foregut carcinoid tumors (bronchial,

thymic, gastrointestinal)

Nonmedullary thyroid neoplasms

Cutaneous/mucosal and visceral

abnormalities (multiple lipomas,

facial angiofibromas, hypomelanotic

macules, gingival papules, collagenomas)

•Diagnosis (clinical) of MEN 1: (1) two major manifestations present

in proband or (2) one major manifestation in an at-risk member of

a known MEN 1 kindred. Confirmation is by genetic testing.

MEN 1 = multiple endocrine neoplasia type 1.

allele with a germline mutation (the "first hit"), and tumori-genesis in specific tissues then occurs after a second deleterious mutation (the "second hit") is acquired in the remaining wildtype allele in a single cell.37 Such homozygous-inactivating MEN1 mutations result in menin protein absence or truncation, and neoplastic clonal expansion from that cell is then initiated. Thus, the mechanism for tumor formation in MEN 1 involves loss of menin function in a tumor precursor cell.

Unlike the RET protooncogene (associated with MEN 2), mutations in MEN1 do not clearly demonstrate significant genotype-phenotype correlations.36'38"40 Recent studies have found preliminary data suggesting that mutation type or location within MEN1 may be associated with clinical presentation.40 However, the limited data available regarding genotype-phenotype correlations do not currently warrant modification of clinical management.

Several analytic approaches to identifying MEN1 mutations have been used, but most laboratories currently use direct DNA sequencing. The first step in the analysis of a sporadic case or a patient in a kindred with suspected or proven MEN 1 is to identify the specific MEN! mutation in germline DNA. Germline testing requires peripheral blood from an affected index case. In most probands, a disease-causing mutation is identified. Because MEN1 somatic mutations are commonly found in endocrine tumors, tumor DNA is rarely useful in distinguishing germline mutations.41"43

It is estimated that more than 10% of germline MEN1 mutations arise de novo and can subsequently be passed to future generations.38'44 Mutations in MEN1 are highly penetrant; approximately 50% of mutation carriers are symptomatic by 20 years of age, and nearly 100% are symptomatic by 60 years of age. Most large series have failed to find MEN1 germline mutations in 10% to 20% of index cases,31'38-44"46 likely reflecting undetected mutations, such as large deletions that are transparent to DNA sequence analysis or mutations in another unknown gene. MEN1 mutational analysis is clinically available in at least four molecular genetics laboratories in North America.

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