MEN1 Gene Mutation and Reduced Expression Are Associated with Poor Prognosis in Pulmonary Carcinoids

Context: MEN1 gene alterations have been implicated in lung carcinoids, but their effect on gene expression and disease outcome are unknown. Objective: To analyse MEN1 gene and expression anomalies in lung neuroendocrine neoplasms (NENs) and their correlations with clinicopathologic data and disease outcome. Design: We examined 74 lung NENs including 58 carcinoids and 16 high-grade neuroendocrine carcinomas (HGNECs) for MEN1 mutations (n=70) and allelic losses (n=69), promoter hypermethylation (n=65), and mRNA (n=74) expression. Results were correlated with disease outcome. Results: MEN1 mutations were found in 7/55 (13%) carcinoids and in 1 HGNEC, mostly associated with loss of the second allele. MEN1 decreased expression levels correlated with the presence of mutations (P=0.0060) and was also lower in HGNECs than carcinoids (P=0.0024). MEN1 methylation was not associated with mRNA expression levels. Patients with carcinoids harbouring MEN1 mutation and loss had shorter overall survival (P=0.039 and P=0.035, respectively), and low MEN1 mRNA levels correlated with distant metastasis (P=0.00010) and shorter survival (P=0.0071). In multivariate analysis, stage and MEN1 allelic loss were independent predictors of prognosis. Conclusion: Thirteen percent of pulmonary carcinoids harbour MEN1 mutation, associated with reduced mRNA expression and poor prognosis. Also in mutation-negative tumours, low MEN1 gene expression correlates with an adverse disease outcome. Hypermethylation was excluded as the underlying mechanism.