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MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma
L V Debelenko1, J I Swalwell, M J Kelley
1Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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 1 (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 MEN1. 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. Published 2000 Wiley-Liss, Inc.
Insights
The MEN1 gene is not frequently inactivated in small-cell lung carcinoma (SCLC) or large-cell neuroendocrine carcinoma (LCNEC). A single LCNEC mutation suggests distinct molecular pathways for lung neuroendocrine tumors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroendocrine tumors of the lung encompass a range of neoplasms, including carcinoids, LCNEC, and SCLC.
- Previous research indicated frequent MEN1 gene inactivation in typical and atypical carcinoid tumors.
- The role of MEN1 gene inactivation in other lung neuroendocrine tumors remained less understood.
Purpose of the Study:
- To investigate MEN1 gene inactivation in primary SCLCs, SCLC cell lines, and primary LCNECs.
- To determine if SCLC and LCNEC share similar MEN1 gene alterations as observed in lung carcinoids.
- To explore the molecular pathways involved in the development of different lung neuroendocrine tumor subtypes.
Main Methods:
- Analysis of loss of heterozygosity (LOH) at the MEN1 gene locus (11q13) in primary tumors and cell lines.
- Screening of the MEN1 gene coding sequence and splice junctions for mutations in all samples.
- Northern blot analysis to assess MEN1 transcript expression in SCLC cell lines.
Main Results:
- No MEN1 gene mutations were detected in 9 primary SCLCs and 36 SCLC cell lines; LOH was found in one primary SCLC and two cell lines.
- MEN1 transcript was present and of normal size in 13 SCLC cell lines.
- A somatic frameshift mutation (1226delC) in the MEN1 gene was identified in one of 13 LCNECs, without evidence of biallelic inactivation.
Conclusions:
- The MEN1 gene is not a frequent target of inactivation in SCLC, suggesting distinct molecular pathogenesis compared to lung carcinoids.
- A single MEN1 gene mutation in LCNEC indicates a potential, albeit uncommon, role in this tumor type, warranting further investigation.
- The findings support the hypothesis that SCLC and lung carcinoids develop through different molecular pathways.