MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma

Larisa V. Debelenko, Jennifer I. Swalwell, Michael J. Kelley, Elisabeth Brambilla, Pachiappan Manickam, Galina Baibakov, Sunita K. Agarwal, Allen M. Spiegel, Stephen J. Marx, Settara C. Chandrasekharappa, Francis S. Collins, William D. Travis, Michael R. Emmert-Buck

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Abstract

Neuroendocrine tumors of the lung consist of a spectrum of neoplasms, including typical carcinoids, atypical carcinoids, large-cell neuroendocrine carcinomas (LCNEC), and small-cell lung carcinomas (SCLC). We previously reported frequent inactivation of the gene responsible for multiple endocrine neoplasia type I (MEN1) in both typical and atypical carcinoid tumors. In the present study, we extend the analysis of human NE lung tumors to include 9 primary SCLCs, 36 SCLC cell lines, and 13 primary LCNECs for MEN1 gene inactivation. In SCLC, loss of heterozygosity (LOH) at the MEN1 gene on chromosome band 11q13 was detected in one primary tumor and two cell lines. The coding sequence and splice junctions of the MEN1 gene were screened for mutations in all 44 tumors and cell lines, and no mutations were detected. Northern blot analysis of 13 SCLC cell lines showed the MEN1 transcript to be present and of normal size. In LCNECs, a somatic frameshift in the MEN1 gene (1226delC) was found in one of 13 tumors, representing the first mutation observed outside the spectrum of neoplasms associated with MEN I. Interestingly, neither a deletion nor a mutation was detected in the other allele, and wild-type mRNA sequence was expressed in the tumor, suggesting that the MEN1 gene was not inactivated by a conventional two-hit mechanism. The data support the hypothesis that SCLC and lung carcinoids develop via distinct molecular pathways; however, further investigation is necessary to determine the significance of the MEN1 gene mutation observed in a single case of LCNEC.

Original languageEnglish (US)
Pages (from-to)58-65
Number of pages8
JournalGenes Chromosomes and Cancer
Volume28
Issue number1
DOIs
StatePublished - May 2000
Externally publishedYes

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Multiple Endocrine Neoplasia Type 1
Neuroendocrine Carcinoma
Lung
Mutation
Small Cell Lung Carcinoma
Genes
Carcinoid Tumor
Large Cell Carcinoma
Gene Silencing
Neoplasms
Tumor Cell Line
Cell Line
Neuroendocrine Tumors
Loss of Heterozygosity
Northern Blotting
Chromosomes
Alleles

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Debelenko, L. V., Swalwell, J. I., Kelley, M. J., Brambilla, E., Manickam, P., Baibakov, G., ... Emmert-Buck, M. R. (2000). MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. Genes Chromosomes and Cancer, 28(1), 58-65. https://doi.org/10.1002/(SICI)1098-2264(200005)28:1<58::AID-GCC7>3.0.CO;2-2

MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. / Debelenko, Larisa V.; Swalwell, Jennifer I.; Kelley, Michael J.; Brambilla, Elisabeth; Manickam, Pachiappan; Baibakov, Galina; Agarwal, Sunita K.; Spiegel, Allen M.; Marx, Stephen J.; Chandrasekharappa, Settara C.; Collins, Francis S.; Travis, William D.; Emmert-Buck, Michael R.

In: Genes Chromosomes and Cancer, Vol. 28, No. 1, 05.2000, p. 58-65.

Research output: Contribution to journalArticle

Debelenko, LV, Swalwell, JI, Kelley, MJ, Brambilla, E, Manickam, P, Baibakov, G, Agarwal, SK, Spiegel, AM, Marx, SJ, Chandrasekharappa, SC, Collins, FS, Travis, WD & Emmert-Buck, MR 2000, 'MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma', Genes Chromosomes and Cancer, vol. 28, no. 1, pp. 58-65. https://doi.org/10.1002/(SICI)1098-2264(200005)28:1<58::AID-GCC7>3.0.CO;2-2
Debelenko, Larisa V. ; Swalwell, Jennifer I. ; Kelley, Michael J. ; Brambilla, Elisabeth ; Manickam, Pachiappan ; Baibakov, Galina ; Agarwal, Sunita K. ; Spiegel, Allen M. ; Marx, Stephen J. ; Chandrasekharappa, Settara C. ; Collins, Francis S. ; Travis, William D. ; Emmert-Buck, Michael R. / MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. In: Genes Chromosomes and Cancer. 2000 ; Vol. 28, No. 1. pp. 58-65.
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AU - Spiegel, Allen M.

AU - Marx, Stephen J.

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AU - Collins, Francis S.

AU - Travis, William D.

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N2 - Neuroendocrine tumors of the lung consist of a spectrum of neoplasms, including typical carcinoids, atypical carcinoids, large-cell neuroendocrine carcinomas (LCNEC), and small-cell lung carcinomas (SCLC). We previously reported frequent inactivation of the gene responsible for multiple endocrine neoplasia type I (MEN1) in both typical and atypical carcinoid tumors. In the present study, we extend the analysis of human NE lung tumors to include 9 primary SCLCs, 36 SCLC cell lines, and 13 primary LCNECs for MEN1 gene inactivation. In SCLC, loss of heterozygosity (LOH) at the MEN1 gene on chromosome band 11q13 was detected in one primary tumor and two cell lines. The coding sequence and splice junctions of the MEN1 gene were screened for mutations in all 44 tumors and cell lines, and no mutations were detected. Northern blot analysis of 13 SCLC cell lines showed the MEN1 transcript to be present and of normal size. In LCNECs, a somatic frameshift in the MEN1 gene (1226delC) was found in one of 13 tumors, representing the first mutation observed outside the spectrum of neoplasms associated with MEN I. Interestingly, neither a deletion nor a mutation was detected in the other allele, and wild-type mRNA sequence was expressed in the tumor, suggesting that the MEN1 gene was not inactivated by a conventional two-hit mechanism. The data support the hypothesis that SCLC and lung carcinoids develop via distinct molecular pathways; however, further investigation is necessary to determine the significance of the MEN1 gene mutation observed in a single case of LCNEC.

AB - Neuroendocrine tumors of the lung consist of a spectrum of neoplasms, including typical carcinoids, atypical carcinoids, large-cell neuroendocrine carcinomas (LCNEC), and small-cell lung carcinomas (SCLC). We previously reported frequent inactivation of the gene responsible for multiple endocrine neoplasia type I (MEN1) in both typical and atypical carcinoid tumors. In the present study, we extend the analysis of human NE lung tumors to include 9 primary SCLCs, 36 SCLC cell lines, and 13 primary LCNECs for MEN1 gene inactivation. In SCLC, loss of heterozygosity (LOH) at the MEN1 gene on chromosome band 11q13 was detected in one primary tumor and two cell lines. The coding sequence and splice junctions of the MEN1 gene were screened for mutations in all 44 tumors and cell lines, and no mutations were detected. Northern blot analysis of 13 SCLC cell lines showed the MEN1 transcript to be present and of normal size. In LCNECs, a somatic frameshift in the MEN1 gene (1226delC) was found in one of 13 tumors, representing the first mutation observed outside the spectrum of neoplasms associated with MEN I. Interestingly, neither a deletion nor a mutation was detected in the other allele, and wild-type mRNA sequence was expressed in the tumor, suggesting that the MEN1 gene was not inactivated by a conventional two-hit mechanism. The data support the hypothesis that SCLC and lung carcinoids develop via distinct molecular pathways; however, further investigation is necessary to determine the significance of the MEN1 gene mutation observed in a single case of LCNEC.

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