Stephen Marx, MD; Allen M. Spiegel, MD; Monica C. Skarulis, MD; John L. Doppman, MD; Francis S. Collins, MD, PhD; Lance A. Liotta, MD, PhD
Multiple endocrine neoplasia type 1 (MEN1) consists of benign, and sometimes malignant, tumors (often multiple in a tissue) of the parathyroids, enteropancreatic neuroendocrine system, anterior pituitary, and other tissues.Skin angiofibromas and skin collagenomas are common. Typically, MEN1 tumors begin two decades earlier than sporadic tumors. Because of tumor multiplicity and the tendency for postoperative tumor recurrence, specialized methods have been developed for preoperative and intraoperative localization of many MEN1-associated tumors.
The MEN1 gene was recently isolated by positional cloning.This strategy progressively narrows the size of the candidate MEN1 gene interval on the chromosome and then finds and tests many or, if needed, all genes within that interval. The MEN1 gene was finally identified because it was the one gene that contained mutations in most DNAs from a test panel of MEN1 cases.
It has been suggested that MEN1, like many hereditary cancer syndromes, is caused by mutation in a tumor suppressor gene that contributes to neoplasia when both gene copies in a tumor precursor cell have been sequentially inactivated (“two-hit” oncogenesis mechanism). Germline MEN1 mutations were found in most families with MEN1 and in most cases of sporadic MEN1. In addition, the MEN1 gene was the gene most likely to show acquired mutation in several sporadic or nonhereditary tumors-parathyroid adenomas, gastrinomas, insulinomas, and bronchial carcinoids. Most germline or acquired MEN1 mutations predicted truncation (and thus likely inactivation) of the encoded protein, supporting expectations for the “first hit” to a tumor suppressor gene. Testing for MEN1 germline mutation is possible in a research setting. Candidates for MEN1 mutation testing include patients with MEN1 or its phenocopies and first-degree relatives of persons with MEN1.
The two copies of chromosome 11 show the inherited DNA pattern (germline nucleus) followed by DNA changes in a tumor precursor cell or a tumor cell (somatic nucleus). The striped compared with the clear copy of chromosome 11 indicates nonidentity at many loci as they derive from genetically unrelated parents. The first hit to the MEN1 gene is generally a small one, such as a point mutation. Although the hit inactivates one copy of the MEN1 gene, it generally has no detectable biological effect on the cell. The first hit can be inherited with the germline, thus being identical in each cell of a case with multiple endocrine neoplasia type 1 (MEN1). Alternately, the first hit can occur as a rare event in any somatic cell nucleus. Thus, the same mutation can contribute to neoplasia on a hereditary or nonhereditary basis. The second hit in a postzygotic or somatic cell typically involves a larger portion of the other, normal copy of chromosome 11. The second hit inactivates the second (or remaining normal) copy of the MEN1 gene by deleting it along with a large zone of contiguous alleles. Sequential inactivation of both copies (two mutations, also termed two hits) of the MEN1 gene removes the brakes to growth in one cell, which may then proliferate to a tumor clone.
Data derived from retrospective analysis for each endocrine organ hyperfunction in 130 cases of MEN1. Age at onset is the age at first symptom or, with tumors not causing symptoms, age at the time of the first abnormal finding on a screening test. The rate of diagnosis of hyperparathyroidism increased sharply between ages 16 and 20 years.
This patient had symptomatic hypergastrinemia and hyperinsulinemia. Large lobulated tumors (approximately 4 cm in diameter) were detected in the pancreatic head and tail ( ). Selective arteriogram with calcium stimulation showed a brisk increase in insulin levels (threefold step-up, not shown) after injection of calcium into the gastroduodenal artery, suggesting that the insulinoma was in the pancreatic head. The adenoma, which was removed from the pancreatic head, stained for insulin. The adenoma in the tail was removed because of its size. It stained only for gastrin. Hyperinsulinemia remitted, and hypergastrinemia continued unchanged.
A. A map spanning approximately 2.8 million bases, part of the long arm of chromosome 11. DNA clones were assembled to span this entire interval. The minimal candidate intervals are shown for the location of the MEN1 gene, as determined separately from pedigree linkage or from loss of heterozygosity (LOH); the loss-of-heterozygosity-derived interval was far smaller. Genetic markers for chromosome 11, which by convention begin with D11, are shown above the line. Various expressed genes are shown by their names or abbreviated names below the line. Alpha, β, and so forth are anonymous new genes assigned Greek letters as temporary names. B. A higher-resolution map featuring the area of maximum interest. A DNA sequence was available from three clones (C1, C2, C3 [C − cosmid]). Heavy horizontal bars below the map indicate the location of clones (b137C7, b79G17, and b18H3 [b = bacterial]), with inserts of human DNA, that were partially sequenced to search for candidate genes. The gene originally designated Mu turned out to be MEN1 . Cen = centromere; Tel = telomere.
A. Schematic diagram of chromosome 11 showing telomeres (Tel), p arm (short arm), centromere (Cen), and q arm (long arm). The cytochemical banding pattern has been used for several decades to localize genes and markers. Early studies of multiple endocrine neoplasia type 1 (MEN1) linked it to the PYGM marker (not shown) at 11q13 (chromosome 11, band q13) . B. The two copies of chromosome 11 from an endocrine tumor and its precursor cell, illustrating the first hit and the second normal copy of chromosome 11 before and after the second hit. The tumor could be from a case with MEN1 or from a case without MEN1 ( ). The second hit caused loss of a large portion of the q arm ( ). Seven DNA markers from ordered loci on chromosome 11, designated A to G, are illustrated. Each one is highly variable (polymorphic). The variants or polymorphisms of each marker are numbered (A1, A2, A3, and so forth). At most markers, the two diagrammed copies of chromosome 11 are heterozygous; they have two different variants (alleles). C. This case is not heterozygous in the germline at markers A and F; those markers are uninformative for this part and therefore are omitted. Markers B, C, and D have two alleles or retention of heterozygosity; markers E and G each have lost one allele. This is termed loss of heterozygosity or allelic loss for those markers. Recognition of loss of heterozygosity could be obscured if the specimen had much DNA from nontumor cells with the germline heterozygous marker patterns.
Partial map of chromosome (Chr) 11q13 shows the relative locations of 16 polymorphic DNA probes. Data are diagrammed from 6 tumors (of 188) that provided loss-of-heterozygosity boundaries, which are helpful for narrowing the candidate interval of the MEN1 gene. Tumors 1 to 4 suggested that the MEN1 gene was located toward the telomere (tel) of the chromosome (telomeric) relative to PYGM. Tumor 6 gave a telomeric boundary at D11S449, and tumor 5 gave a narrower telomeric boundary at D11S4936. The region between PYGM and D11S4936, the minimal MEN1 candidate interval, is approximately 0.3 million bases . The same major landmarks are shown in . Cen = centromere. Black squares = allelic retention; white squares = loss of heterozygosity at an informative marker.
Locations are shown on the horizontal bar containing MEN1 exons for germline MEN1 mutation in 56 kindreds and for somatic MEN1 mutation in seven parathyroids, nine gastrinomas, two insulinomas, four bronchial carcinoids, and two pituitary tumors . Mutations shown above the exons cause protein truncation through stop codon or frameshift (small insertion or deletion), leading to a premature stop codon, two cause splice error. Those shown below the exons cause missense or one amino acid-codon change, by base substitution or by deletion of three bases without changing the triplet reading frame. Mutation descriptions follow standard nomenclature ( ; see Glossary). bp = base pair; NIH = National Institutes of Health.
Marx S, Spiegel AM, Skarulis MC, et al. Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics. Ann Intern Med. 1998;129:484–494. doi: https://doi.org/10.7326/0003-4819-129-6-199809150-00011
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Published: Ann Intern Med. 1998;129(6):484-494.
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