Expression Analysis of Genes Involved in DNA Repair or Synthesis in mixed Neuroendocrine/Non-Neuroendocrine Carcinomas

Background: Mixed Neuroendocrine/non-neuroendocrine carcinomas are heterogeneous tumors having poorly defined diagnostic and clinical features and lacking pathological or molecular markers of prognosis or predictive of response to therapy. We aimed at analyzing the pathological features and the expression of genes involved in DNA repair or synthesis in a cohort of mixed carcinomas from different sites, as compared to patients' outcome. Methods: Relative cDNA quantification of ribonucleotide reductase large subunit 1, excision repair cross-complementation group 1, thymidylate synthase and topoisomerase IIa genes was tested using real-time PCR in micro-dissected neuroendocrine and non-neuroendocrine tumor components of mixed cases (42 cases enrolled, from lung, gastrointestinal and genitourinary tract) and in 45 control cases of pure neuroendocrine and non-neuroendocrine carcinomas. Results: Expression levels of all genes were stable comparing non-neuroendocrine and neuroendocrine components of mixed cases (except for topoisomerase IIa in lung samples), but significantly different as compared to control non-neuroendocrine and neuroendocrine tumors. At multivariate analysis, including all available clinical and pathological parameters and gene expression levels, predominant non-neuroendocrine component, administration of additional therapy other than surgery and high thymidylate synthase expression in non-NE tumor tissue were significantly associated to a lower risk of patient's death. Conclusions: Our data show that mixed neuroendocrine/non-neuroendocrine carcinomas are different at the molecular level from their corresponding pure neuroendocrine and non- neuroendocrine counterparts, and detailed analysis of clinical, pathological and molecular features may improve the clinical strategies in these rare and underestimated tumors