MENI gene mutation analysis of high-grade neuroendocrine lung carcinoma

Neuroendocrine tumors of the lung consist of a spectrum of neoplasms, inclu ding typical carcinoids, atypical carcinoids, large-cell neuroendocrine car cinomas (LCNEC), and small-cell lung carcinomas (SCLC). We previously repor ted frequent inactivation of the gene responsible for multiple endocrine ne oplasia type I (MENI) 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 MENI gene ina ctivation. In SCLC, loss of heterozygosity (LOH) at the MENI gene on chromo some band 11q13 was detected in one primary tumor and two cell lines. The c oding sequence and splice junctions of the MENI gene were screened for muta tions in all 44 tumors and cell lines, and no mutations were detected. Nort hern blot analysis of 13 SCLC cell lines showed the MENI transcript to be p resent and of normal size. In LCNECs, a somatic frameshift in the MENI gene (1226delC) was found in one of 13 tumors, representing the first mutation observed outside the spectrum of neoplasms associated with MENI. Interestin gly, neither a deletion nor a mutation was detected in the other allele, an d wild-type mRNA sequence was expressed in the tumor, suggesting that the M ENI gene was not inactivated by a conventional two-hit mechanism. The data support the hypothesis chat SCLC and lung carcinoids develop via distinct m olecular pathways; however, further investigation is necessary to determine the significance of the MENI gene mutation observed in a single case of LC NEC. Genes Chromosomes Cancer 28:58-65, 2000. Published 2000 Wiley-Liss, In c.