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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.