Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Debelenko, Larisa V.; Brambilla, Élisabeth; Agarwal, Sunita K.; Swalwell, Jennifer I.; Kester, Mary Beth; Lubensky, Irina A.; Zhuang, Zhengping; Guru, Siradanahalli C.; Manickam, Pachiappan; Olufemi, Shodimu-Emmanuel; Chandrasekharappa, Settara C.; Crabtree, Judy S.; Kim, Young S.; Heppner, Christina; Burns, A. Lee; Spiegel, Allen M.; Marx, Stephen J.; Liotta, Lance A.; Collins, Francis S.; Travis, William D.; Emmert‐Buck, Michael R.

doi:10.1093/hmg/6.13.2285

Cited by 238 publications

(133 citation statements)

References 23 publications

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“…Sporadic lung carcinoids and pancreatic endocrine tumors frequently display allelic losses at 11q13, and somatic MEN1 mutations have been revealed in approximately one-third of these tumors. 3,4 Combining results from previous studies, loss of heterozygosity (LOH) on chromosome 11 has been detected in 3/13 midgut carcinoids, a somatic missense MEN1 mutation in 1/16 lesions and microsatellite instability in 1/6 lesions. 5-9 p53 mutations are rare, and K-ras mutations appear to be absent in midgut carcinoids.…”

mentioning

confidence: 71%

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

et al. 2001

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Classical midgut carcinoids are rare intestinal neuroendocrine tumors that often present with metastases at diagnosis. In contrast to foregut carcinoids, midgut carcinoids are not related to the multiple endocrine neoplasia type 1 syndrome, and the mechanisms involved in their tumorigenesis are unknown. Eight classical midgut carcinoids were analyzed by genome-wide screening for loss of heterozygosity. Deletions on chromosome 18 were found in 88% of the tumors. DNA sequencing and immunohistochemical staining for Smad4/ DPC4, which often is homozygously mutated in pancreatic and colon carcinomas, revealed no aberrations. In 1 tumor, a region telomeric to the Smad4/DPC4/DCC genes at 18q21 was deleted. Other chromosomes were affected in 3 lesions only. The high frequency of chromosome 18 deletions strongly indicates a genetic alteration of importance in classical midgut carcinoid tumorigenesis, apparently not involving the Smad4/DPC4 gene.

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confidence: 71%

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

et al. 2001

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“…Compiled rates of allelic loss are 10 to 18% in sporadic pituitary adenomas, 39% in parathyroid tumors, 51 to 92% in endocrine enteropancreatic tumors, and 60% in carcinoid tumors of the lung and gastrointestinal tract. 5,20,22,23 The incidence of 11q13 LOH in sporadic mesenchymal counterpart tumors, however, is uncertain because of small sample size. 24 Table 2.…”

Section: Discussionmentioning

confidence: 99%

Multiple Leiomyomas of the Esophagus, Lung, and Uterus in Multiple Endocrine Neoplasia Type 1

McKeeby

Zhuang

et al. 2001

The American Journal of Pathology

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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. The gene for multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant tumor syndrome, has been mapped to chromosome 11q13 1 and recently identified. 2 The MEN1 gene is thought to act as a tumor suppressor based on the presence of inherited inactivating mutations in the constitutional DNA of affected family members accompanied by the loss of the wild-type allele in associated tumors. 2-4 Somatic inactivation of the MEN1 gene has been also documented in a subset of sporadic counterpart parathyroid, enteropancreatic, and pulmonary endocrine tumors, and mesenchymal tumors. 5 MEN1 patients typically present first with primary hyperparathyroidism resulting from multiple parathyroid tumors caused by MEN1 gene alterations. 6 Neuroendocrine tumors of the pancreas, duodenum, anterior pituitary gland, stomach, and lung are other tumors that are an integral part of MEN1. 7,8 Nonendocrine mesenchymal tumors, such as lipomas, angiofibromas, and collagenomas, have also been shown to be associated with MEN1 and MEN1 gene alterations. 8 -10 Leiomyomata have been occasionally documented in MEN1 patients, 8,[11][12][13][14] and loss of heterozygosity (LOH) at the MEN1 locus was recently shown in two esophageal leiomyomata from one MEN1 patient. 15 MEN1 gene inactivation in lung or uterine leiomyomata, however, has not been studied. To test whether MEN1 gene alterations are involved in the development of multiple smooth muscle tumors in MEN1 patients, we analyzed 15 leiomyomata from five patients with documented MEN1 germline mutations for LOH at the MEN1 gene locus. To assess whether MEN1 gene alterations are present in sporadic smooth muscle tumors, we analyzed 40 sporadic uterine leiomyomata for MEN1 gene deletion for comparison. Furthermore, to evaluate whether MEN1-associated leiomyomata arise as independent clonal events at different anatomical sites within an organ, the patterns of 11q13 LOH in different tumors from individual patients

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“…In pulmonary carcinoids, an interesting subset of endocrine tumors, similar MEN1 alterations have been reported and considered to be involved in the development of these tumors (17)(18)(19)(20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 68%

“…Alterations of the MEN1 gene occur in a great variety of endocrine tumors and they are considered also to be involved in the pathogenesis of pulmonary carcinoids (17)(18)(19)(20)(21)(22)(23)(24). Specifically, allelic deletions and mutations of the MEN1 gene have been reported in lung carcinoid tumors, including those developing sporadically in the absence of MEN1 syndrome (17,20,24).…”

Section: Discussionmentioning

confidence: 99%

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Microsatellite instability and loss of heterozygosity at the MEN1 locus in lung carcinoid tumors: A novel approach using real-time PCR with melting curve analysis in histopathologic material

Vageli¹,

Daniil²,

Dahabreh³

et al. 2006

Oncol Rep

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Abstract. The possible causes and genetic mechanisms of pulmonary carcinoid tumor development are unclear. In this study, we examined genetic alterations at the MEN1 locus in archival material from 15 pulmonary carcinoids. We employed, for the first time in this setting, real-time PCR with melting curve analysis in order to identify loss of heterozygosity (LOH) or microsatellite instability (MI) in two polymorphic markers (PYGM, D11S449) at the MEN1 locus and one additional marker (D11S906) of a putative oncosuppressive region distal to the MEN1 gene. Sequencing data were available in a selected subset of tumors in order to verify the reliability of real-time PCR analysis. We observed LOH at PYGM in 38% of the cases and MI in 13.3% of the cases. Our data indicate that real-time PCR with melting curve analysis is a reliable technique for LOH and MI detection and indicate that genetic errors at the MEN1 locus but also distal to it may be involved in the development of sporadic pulmonary carcinoid tumors.

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Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Cited by 238 publications

References 23 publications

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

Chromosome 18 deletions are common events in classical midgut carcinoid tumors

Multiple Leiomyomas of the Esophagus, Lung, and Uterus in Multiple Endocrine Neoplasia Type 1

Microsatellite instability and loss of heterozygosity at the MEN1 locus in lung carcinoid tumors: A novel approach using real-time PCR with melting curve analysis in histopathologic material

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