1. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Sequential inactivation of both copies of the MEN1 gene contributes to hereditary or common variety tumor.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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

2. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Age at onset of endocrine tumor expression in multiple endocrine neoplasia type 1 (MEN1).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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

3. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Computed tomogram of the abdomen in multiple endocrine neoplasia type 1.arrowsThis 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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

4. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Candidate interval for MEN1 gene.[42]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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

5. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Method to map from tumors the zone of loss of heterozygosity (LOH) at chromosome 11q13.[8]Figure 1dashed linesA. 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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

6. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Boundaries of loss of heterozygosity in endocrine tumors narrowed the chromosomal interval for the MEN1 gene hunt.[46]Figure 4Partial 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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians

7. Date of download: 6/2/2016 From: Multiple Endocrine Neoplasia Type 1: Clinical and Genetic Topics Ann Intern Med. 1998;129(6):484-494. doi:10.7326/0003-4819-129-6-199809150-00011 Compilation of germline and somatic MEN1 mutations.[48-51][53-56][57]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. Figure Legend: Copyright © American College of Physicians. All rights reserved.American College of Physicians