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. 2001 Sep;159(3):1121-7.
doi: 10.1016/S0002-9440(10)61788-9.

Multiple leiomyomas of the esophagus, lung, and uterus in multiple endocrine neoplasia type 1

J L McKeeby  1 , X Li, Z Zhuang, A O Vortmeyer, S Huang, M Pirner, M C Skarulis, L James-Newton, S J Marx, I A Lubensky
Affiliations

Multiple leiomyomas of the esophagus, lung, and uterus in multiple endocrine neoplasia type 1

J L McKeeby et al. Am J Pathol. 2001 Sep.

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by multiple parathyroid, pancreatic, duodenal, and pituitary neuroendocrine tumors. Nonendocrine mesenchymal tumors, such as lipomas, collagenomas, and angiofibromas have also been reported. MEN1-associated neuroendocrine and some mesenchymal tumors have documented MEN1 gene alterations on chromosome 11q13. To test whether the MEN1 gene is involved in the pathogenesis of multiple smooth muscle tumors, we examined the 11q13 loss of heterozygosity (LOH) and clonality patterns in 15 leiomyomata of the esophagus, lung, and uterus from five patients with MEN1. Forty sporadic uterine leiomyomata were also studied for 11q13 LOH. LOH analysis was performed using four polymorphic DNA markers at the MEN1 gene locus; D11S480, PYGM, D11S449, and INT-2. 11q13 LOH was detected in 10 of 12 (83%) MEN1-associated esophageal and uterine smooth muscle tumors. In contrast, LOH at the MEN1 gene locus was demonstrated only in 2 of 40 (5%) sporadic uterine tumors. LOH at 11q13 was not documented in three lung smooth muscle tumors from a single patient with MEN1. Ten tumors from two female patients were additionally assessed for clonality by X-chromosome inactivation analysis. The results demonstrated different clonality patterns in multiple tumors in the same organ in each individual patient. The data indicate that leiomyomata of the esophagus and uterus in MEN1 patients arise as independent clones, develop through MEN1 gene alterations, and are an integral part of MEN1. However, the MEN1 gene is not a significant contributor to the tumorigenesis of sporadic uterine leiomyomata.

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Figures

Figure 1.
Figure 1.
Representative results of 11q13 LOH in multiple leiomyomata in four MEN1 patients. Polymorphic markers (D11S480, PYGM, D11S449, INT-2) at the MEN1 gene locus. Tumor number corresponds to the tumor number in Table 2▶ : T1, esophageal tumor in patient 1; T2 and T3, esophageal tumors in patient 2; T4 to T6, uterine tumors in patient 3; T7 to T9, lung tumors in patient 4; T10, esophageal tumor in patient 4; T11 to T13, uterine tumors in patient 4. Arrowhead indicates the position of the two alleles. Deletion of the lower allele with marker D11S480 was detected in tumor T1 in patient 1 and in tumors T2 and T3 in patient 2. Deletion of the upper allele with marker D11S480 was detected in tumors T4 and T5 in patient 3. For marker PYGM, deletion of the lower allele was seen in tumors T2 and T3 in patient 2 (PYGM(CAGA)) and T11 to T13 in patient 4 (PYGM(AT)). Tumors T7, T8, T10 in patient 4 showed retention of heterozygosity with PYGM. For marker D11S449, the lower allele was deleted in T2 and T3 in patient 2. In patient 4, tumors T11 and T13 demonstrated loss of the lower allele, whereas tumors T7 to T10, and T12 retained heterozygosity with D11S449. Loss of the lower allele in T2 and T3 in patient 2 is seen with marker INT-2. N, matched normal tissue from each patient.
Figure 2.
Figure 2.
Representative results of the X-chromosome inactivation analysis of 10 tumors in two female patients. The X-chromosome inactivation method (HUMARA) was used to evaluate clonality of separate tumors. In patient 3, uterine tumor T4 shows methylation of the upper allele and methylation of the lower alleles in uterine tumors T5 and T6. In patient 4, uterine tumor T11 shows methylation of the upper allele, and uterine tumors T12 and T13 show lower allele methylation. At least two of the uterine tumors in each patient arise independently as a different clone. Tumor number corresponds to the tumor number in Table 2▶ . N, normal control, undigested (−) or digested (+), with restriction endonuclease HpaII.
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