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Detection of MAGE-A Transcripts in Bone Marrow Is an Independent Prognostic Factor in Operable Non–Small-Cell Lung Cancer

Authors' Affiliations: ¹ Department of Thoracic Surgery, Albert-Ludwigs University Freiburg, Freiburg, Germany; ² Institute for Immunology, Ludwig-Maximilians University Munich, Munich, Germany; and ³ Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Requests for reprints: Wulf Sienel, Department of Thoracic Surgery, University Hospital Freiburg, Albert-Ludwigs-University Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany. Phone: 49-761-270-2401; Fax: 49-761-270-2499; E-mail: wulf.sienel{at}uniklinik-freiburg.de.

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., pT_1-4 pN_0-2 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.