Detection of MAGE-A transcripts in bone marrow is an independent prognostic factor in operable non-small-cell lung cancer

Abstract

Purpose: MAGE-A gene expression in humans is mostly restricted to tumor cells, and the role of MAGE-A transcripts and peptides as diagnostic markers and therapeutic targets is currently under investigation. Thus far, the clinical relevance of MAGE-A transcripts as marker for disseminated tumor cells in bone marrow of patients with operable lung cancer without overt metastases is still unclear. Experimental Design: Preoperative bone marrow aspirates from 50 consecutive patients with operable non - small-cell lung cancer free of distant metastases (i.e., pT1-4 pN0-2 M0 R0) were admitted to the study. Each bone marrow sample was divided and examined using multimarker MAGE-A reverse transcription-PCR (RT-PCR) and immunocytochemical staining with the anti-pancytokeratin antibody A45-B/B3. Multimarker MAGE-A RT-PCR consisted of multiple subtype-specific nested RT-PCRs with primers for MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12. The median follow-up duration was 92 months (range, 18-110 months). Results: Twenty-six (52%) lung cancer patients harbored MAGE-A transcripts in their bone marrow, as opposed to none of the 30 healthy controls tested. In all 7 patients with immunocytochemically positive bone marrow, MAGE-A transcripts were also detected. All different MAGE-A subtypes (MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12) were observed. Sixty-five percent of patients with MAGE-A transcripts in bone marrow exhibited only one subtype. Univariate (P = 0.03, log-rank-test) and multivariate survival analysis showed that MAGE-A transcripts in bone marrow were associated with poor outcome in pN0 patients (P = 0.02; relative risk, 7.6). Conclusions: Detection of MAGE-A transcripts in bone marrow predicts an unfavorable outcome in patients with early-stage operable lung cancer. This finding indicates that MAGE-A transcripts are clinically relevant markers of micrometastatic spread in lung cancer and supports further investigation of MAGE-A as potential future therapeutic target. © 2007 American Association for Cancer Research.