Originally published as JCO Early Release 10.1200/JCO.2008.17.9762 on March 30 2009

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Multicenter Validation of a 1,550-Gene Expression Profile for Identification of Tumor Tissue of Origin

From The Methodist Hospital and The Methodist Hospital Research Institute, Houston, TX; the Clinical Genomics Facility and Department of Pathology, University of Pittsburgh, Pittsburgh, PA; Pathwork Diagnostics, Sunnyvale, CA; Department of Pathology, VA Commonwealth University, Richmond, VA; and the Department of Laboratory Medicine and Pathology, Division of Laboratory Genetics, Mayo Clinic, Rochester, MN.

Corresponding author: Federico A. Monzon, MD, Medical Director of Molecular Diagnostics, The Methodist Hospital, 6565 Fannin St, MS 205, Houston, TX 77030; e-mail: famonzon{at}tmhs.org.

Purpose Malignancies found in unexpected locations or with poorly differentiated morphologies can pose a significant challenge for tissue of origin determination. Current histologic and imaging techniques fail to yield definitive identification of the tissue of origin in a significant number of cases. The aim of this study was to validate a predefined 1,550-gene expression profile for this purpose.

Methods Four institutions processed 547 frozen specimens representing 15 tissues of origin using oligonucleotide microarrays. Half of the specimens were metastatic tumors, with the remainder being poorly differentiated and undifferentiated primary cancers chosen to resemble those that present as a clinical challenge.

Results In this blinded multicenter validation study the 1,550-gene expression profile was highly informative in tissue determination. The study found overall sensitivity (positive percent agreement with reference diagnosis) of 87.8% (95% CI, 84.7% to 90.4%) and overall specificity (negative percent agreement with reference diagnosis) of 99.4% (95% CI, 98.3% to 99.9%). Performance within the subgroup of metastatic tumors (n = 258) was found to be slightly lower than that of the poorly differentiated and undifferentiated primary tumor subgroup, 84.5% and 90.7%, respectively (P = .04). Differences between individual laboratories were not statistically significant.

Conclusion This study represents the first adequately sized, multicenter validation of a gene-expression profile for tissue of origin determination restricted to poorly differentiated and undifferentiated primary cancers and metastatic tumors. These results indicate that this profile should be a valuable addition or alternative to currently available diagnostic methods for the evaluation of uncertain primary cancers.

Supported by a sponsored research agreement from Pathwork Diagnostics, Sunnyvale, CA (F.A.M., with a subcontract to C.I.D.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Presented in part in poster format at the Annual Meeting of the Association for Molecular Pathology, Los Angeles, CA, November 7-10, 2007; and the Annual Meeting of the United States and Canadian Academy of Pathology, San Diego, CA, March 24-30, 2007.

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