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Identification of Cervical Cancer Markers by cDNA and Tissue Microarrays

Departments of Molecular and Cell Biology [Y. C., C. M., R. Mo., X. Z., J. D., D. Y., R. Me., F. C., R. S.] and Applied Bioinformatics [M. M., B. B.], Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139; Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota 55905 [B. S. G.]; and Department of Obstetrics, Gynecology and Reproductive Sciences and Cancer Research Institute, University of California at San Francisco Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-0128 [K. S-M.]

The Pap test has effectively reduced the incidence and mortality of cervical cancer. However, because of the morphological basis of this test, sensitivity and specificity are less than ideal, a situation that complicates the clinical management of women diagnosed with low-grade cervical abnormalities. In an attempt to understand the molecular basis of cervical tumorigenesis and to discover molecular markers for accurate cervical cancer screening, we used cDNA microarrays containing >30,000 Unigene clones to examine the gene expression patterns of 34 cervical tissues from different clinically defined stages. It was found that global gene expression patterns separated normal cervical tissues and low-grade squamous intraepithelial lesions from cervical cancers and most of the high-grade squamous intraepithelial lesions (HSILs). Among the top 62 genes/(expressed sequence tags) that were overexpressed in tumors and HSIL tissues, 35 were confirmed using in situ hybridization on cervical tissue micorarrays. Many of these genes were overexpressed in high-grade dysplastic and malignant cervical epithelium or in stroma adjacent to the diseased tissues, with cellular proliferation and extracellular matrix-associated genes being the most common. In general, the extent of gene overexpression increased as the lesions progressed from low-grade squamous intraepithelial lesions to HSILs and finally to cancer. It is hoped that with additional development, some of these markers will improve the interpretation of cervical screening tests and provide useful information for patient management decisions.

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