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Validation of Genomics-Based Prognostic Tests in Malignant Pleural Mesothelioma

Authors' Affiliations: ¹ Thoracic Surgery Oncology Laboratory and Division of Thoracic Surgery and ² Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; ³ Department of Physics, University of Massachusetts; ⁴ Hematology/Oncology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; and ⁵ Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts

Requests for reprints: Gavin J. Gordon or Raphael Bueno, Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-8148; Fax: 617-582-6171; E-mail: ggordon{at}partners.org or rbueno{at}partners.org.

Purpose: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm with limited pretreatment prognostication strategies. In this report, we examine the accuracy of a previously proposed prognostic test in an independent cohort of MPM patients. This test uses simple ratios of gene expression levels to provide a novel prognostication scheme.

Experimental Design: Gene expression data using high-density oligonucleotide microarrays (22,000 genes) were obtained for a new cohort of human MPM tumors from patients undergoing similar treatments (n = 39). The relative expression levels for specific genes were also determined using real-time quantitative reverse transcription-PCR. We also used a subset of these tumors associated with widely divergent patient survival (n = 23) as a training set to identify new treatment-specific candidate prognostic molecular markers and gene ratio–based prognostic tests. The predictive nature of these newly discovered markers and gene ratio–based prognostic tests were then examined in an independent group of tumors (n = 52) using microarray data and quantitative reverse transcription-PCR.

Results: Previously described MPM prognostic genes and gene ratio–based prognostic tests predicted clinical outcome in 39 independent MPM tumor specimens in a statistically significant manner. Newly discovered treatment-specific prognostic genes and gene ratio–based prognostic tests were highly accurate and statistically significant when examined in an independent group of 52 tumors from patients undergoing similar treatment.

Conclusions: The data support the use of gene ratios in translating gene expression data into easily reproducible, statistically validated clinical tests for the prediction of outcome in MPM.

Key Words: expression profiling • prognosis • gene ratios

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