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Markers of Adenocarcinoma Characteristic of the Site of Origin: Development of a Diagnostic Algorithm

Authors' Affiliations: ¹ Cancer Research UK Centre for Oncology and Applied Pharmacology; ² Department of Statistics and ³ Division of Cancer Sciences and Molecular Pathology, University of Glasgow; ⁴ Department of Pathology, Glasgow Royal Infirmary, Glasgow; ⁵ Department of Pathology, St. James' Hospital, Leeds; ⁶ Department of Pathology, University of Edinburgh, Edinburgh, United Kingdom; and ⁷ Linnaeus Centre for Bioinformatics, University of Uppsala, Uppsala, Sweden

Requests for reprints: Karin A. Oien, Centre for Oncology and Applied Pharmacology, Cancer Research UK, Beatson Laboratories, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, United Kingdom. Phone: 44-141-330-3506; Fax: 44-141-330-4127; E-mail: k.oien{at}beatson.gla.ac.uk.

Purpose: Patients with metastatic adenocarcinoma of unknown origin are a common clinical problem. Knowledge of the primary site is important for their management, but histologically, such tumors appear similar. Better diagnostic markers are needed to enable the assignment of metastases to likely sites of origin on pathologic samples.

Experimental Design: Expression profiling of 27 candidate markers was done using tissue microarrays and immunohistochemistry. In the first (training) round, we studied 352 primary adenocarcinomas, from seven main sites (breast, colon, lung, ovary, pancreas, prostate and stomach) and their differential diagnoses. Data were analyzed in Microsoft Access and the Rosetta system, and used to develop a classification scheme. In the second (validation) round, we studied 100 primary adenocarcinomas and 30 paired metastases.

Results: In the first round, we generated expression profiles for all 27 candidate markers in each of the seven main primary sites. Data analysis led to a simplified diagnostic panel and decision tree containing 10 markers only: CA125, CDX2, cytokeratins 7 and 20, estrogen receptor, gross cystic disease fluid protein 15, lysozyme, mesothelin, prostate-specific antigen, and thyroid transcription factor 1. Applying the panel and tree to the original data provided correct classification in 88%. The 10 markers and diagnostic algorithm were then tested in a second, independent, set of primary and metastatic tumors and again 88% were correctly classified.

Conclusions: This classification scheme should enable better prediction on biopsy material of the primary site in patients with metastatic adenocarcinoma of unknown origin, leading to improved management and therapy.

Key Words: Pathology • Immunohistochemistry • Metastasis/metastasis genes/metastasis models • Molecular diagnosis and prognosis • Molecular markers of metastasis and progression

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