Retinoic Acid Receptor-Beta as a Prognostic Indicator in Stage I Non–Small-Cell Lung Cancer

Abstract

PURPOSE: Retinoids are pivotal in the growth and differentiation of certain epithelial tissues, interacting with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors. RAR-beta mRNA is undetectable by in situ hybridization (ISH) in 50% of non–small-cell lung cancers (NSCLC). RAR-β may suppress tumorigenicity. Therefore, we hypothesized that loss of expression of RAR-β gene in stage I NSCLC is a prognostic factor of a poor clinical outcome.PATIENTS AND METHODS: We retrospectively analyzed RAR-β mRNA levels (by ISH using a digoxigenin-labeled antisense riboprobe) in specimens from 185 consecutive patients with completely resected clinical/radiographic stage I NSCLC for whom clinical follow-up data were available.RESULTS: One hundred fifty-six patients who met the criteria of pathologic stage I NSCLC and positivity for RXR-alpha mRNA (used as a control to assess RNA degradation) and who had adequate follow-up could be evaluated. RAR-β mRNA expression was undetectable in 51 patients, weakly positive in 64 patients, and strongly positive in 41 patients. Overall survival of the 41 patients with strongly positive RAR-β was significantly worse than for the 115 patients with weak or absent RAR-β (P = .045).CONCLUSION: Unexpectedly, strong RAR-β expression was associated with a significantly worse outcome of early-stage NSCLC. The mechanisms underlying this clinically and biologically important finding should be further explored.