Molecular characteristics of ERCC1 negative vs. ERCC1 positive tumors in resected NSCLC

PURPOSE: ERCC1 is a protein involved in repair of DNA platinum adducts and stalled DNA replication forks. We and others have previously demonstrated the influence of ERCC1 expression upon survival rates and benefit of cisplatin-based chemotherapy in patients with resected non-small cell lung cancer (NSCLC). However little is known about the molecular characteristics of ERCC1 positive and negative tumors. EXPERIMENTAL DESIGN: We took advantage of a cohort of 91 patients with resected non-small cell lung cancer for which we had matched frozen and paraffin-embedded samples to explore the comparative molecular portraits of ERCC1 positive and negative tumors of NSCLC. We performed a global molecular analysis including assessment of ERCC1 expression levels using both immunohistochemistry (IHC) and quantitative RT-PCR, genomic instability (CGH), global gene and miRNA expression and sequencing of selected key genes involved in lung carcinogenesis. RESULTS: ERCC1 protein and mRNA expression were significantly correlated. However, we observed several cases with clear discrepancies. We noted that ERCC1 negative-tumors had a higher rate of genomic abnormalities vs. ERCC1 positive-tumors. ERCC1 positive-tumors seemed to share a common DNA-damage response phenotype with the overexpression of 7 genes linked to DNA-damage response. The miRNA expression analysis identified miR-375 as significantly under-expressed in ERCC1 positive-tumors. CONCLUSIONS: Our data demonstrate inconsistencies in ERCC1 expression between IHC and qRT-PCR readouts. Further, ERCC1 status is not linked to specific mutational patterns or frequencies. Finally, ERCC1-negative tumors have a high rate of genomic aberrations that could consequently influence prognosis in patients with resected NSCLC. Research. on October 16, 2017. © 2011 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July 12, 2011; DOI: 10.1158/1078-0432.CCR-11-0790