Gene expression in papillary thyroid carcinoma reveals highly consistent profiles.
Journal: 2002/January - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase-PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET, LGALS3, KRT19, DPP4, MDK, TIMP1, and FN1. The numerous additional genes include CITED1, CHI3L1, ODZ1, N33, SFTPB, and SCEL. Reverse transcriptase-PCR showed high expression of CITED1, CHI3L1, ODZ1, and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.
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Proc Natl Acad Sci U S A 98(26): 15044-15049

Gene expression in papillary thyroid carcinoma reveals highly consistent profiles

+3 authors
Human Cancer Genetics Program, Comprehensive Cancer Center, Department of Pathology, Divisions of Sensory Biophysics and Endocrinology and Nuclear Medicine, Ohio State University, Columbus, OH 43210; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
To whom reprint requests should be addressed at: Human Cancer Genetics Program, Comprehensive Cancer Center, Ohio State University, Room 646, Tzagournis Medical Research Facility, 420 West 12th Avenue, Columbus, OH 43210. E-mail: ude.uso.rtcdem@1-ellepahcaled.
Contributed by Albert de la Chapelle
Contributed by Albert de la Chapelle
Accepted 2001 Oct 15.

Abstract

Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase–PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET, LGALS3, KRT19, DPP4, MDK, TIMP1, and FN1. The numerous additional genes include CITED1, CHI3L1, ODZ1, N33, SFTPB, and SCEL. Reverse transcriptase–PCR showed high expression of CITED1, CHI3L1, ODZ1, and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.

Abstract

Approximately 19,500 new cases of thyroid carcinoma are diagnosed each year in the United States, and 1,300 patients die of the disease (1). Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, accounting for about 80% of all thyroid cancers in the United States (2). The biological behavior of PTC varies widely, from indolent microcarcinomas, growing slowly with little or no invasion, to invasive tumors that metastasize and can cause death.

Although the etiology of PTC is generally poorly understood, a strong association exists with exposure to ionizing radiation in a minority of cases (3). Evidence from regions heavily contaminated by downfall from the Chernobyl accident show 100- to 200-fold increases in PTC, mainly in children (4). Most cases of PTC are sporadic, but as many as 6% of patients have a family history of PTC (5). Among all cancers not displaying regular Mendelian inheritance, thyroid cancer has the highest relative risk (8.60) for first-degree relatives of probands (6). These facts suggest the involvement of specific genes, including tumor suppressor genes and predisposing genes. However, genes, signaling pathways, and other basic mechanisms are currently poorly defined (7). Another shortcoming is the paucity of diagnostic and prognostic biomarkers.

This study was undertaken as a step toward identifying previously uncharacterized molecular genetic mechanisms in PTC. We chose to first analyze the levels of mRNA for more than 12,000 transcripts by microarray hybridization. Results from eight PTC tumors were compared with normal thyroid tissue from the same eight individuals. For selected genes the changes in expression were confirmed by semiquantitative reverse transcriptase (RT)-PCR. Protein expression was studied by immunohistochemistry in tumors from the eight patients and in additional tumors. We detected differential expression of genes that were previously known to be altered in PTC, validating the feasibility of our experimental approach. Numerous novel genes were found to be differentially expressed, some of them in a high proportion of the PTCs. For ease of discussion, we use the terms overexpression and underexpression to describe increased and decreased expression levels in the PTCs.

The data shown are the number of samples with positive staining/total number of samples. All the tissues are from a tissue microarray, except those marked by

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Acknowledgments

We thank Drs. David Schuller and William Farrar for allowing us to use specimens they provided and Dr. Toshi Shioda for providing rabbit polyclonal anti-CITED1 antibody. This work was supported by Grant CA 16058 from the National Institutes of Health.

Acknowledgments

Abbreviations

PTCpapillary thyroid carcinoma
RTreverse transcriptase
Abbreviations

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