Genome-Wide Expression Profiling Reveals Downregulation of OTP and CD44 and Upregulation of RET as Indicators of Poor Prognosis in Lung Carcinoids.

Introduction: Lung carcinoids comprise a heterogeneous group of neuroendocrine tumors. Only few parameters have been identified that correlated with poor disease outcome, including 11q22-q25 deletions. New biomarkers are required to further improve diagnosis and prediction of prognosis. Aim(s): To identify differentially expressed genes between carcinoids with a favorable and poor outcome using high resolution gene-expression profiling, and to test their value as prognostic markers. Materials and methods: mRNA of five tumors with a favorable (>5yr survival) and five with a poor (distant metastasis / deceased) disease outcome was labeled and hybridized to 4x44k Agilent arrays, with a human pool expressing 70-80% of genes as a control. Results were validated by qRT-PCR and immunohistochemistry on an independent series of lung carcinoids. Results: Expression profiling revealed amongst others overexpression of the RET oncogene and repression of the homeobox gene OTP and CD44 in the poor prognosis group. In 54 frozen cases, low CD44 (p<0.0001) and OTP (p=0.0013), and high RET (p=0.0035) expression were significantly associated with decreased 15-year survival, outperforming WHO classification. Downregulation of CD44 and OTP expression was confirmed in tumors with a poor prognosis by immunohistochemistry. Conclusion: High resolution expression profiling unmasked new lung carcinoid candidate genes, of which CD44, OTP, and RET efficiently predict poor outcome. [ABSTRACT FROM AUTHOR]