Gene Expression Profiling of Papillary Thyroid Carcinoma Identifies Transcripts Correlated with BRAF Mutational Status and Lymph Node Metastasis

• Published in: Clinical cancer research Vol. 14; no. 15; pp. 4735 - 4742
• Main Authors: Gisele Oler, Cléber P. Camacho, Flávio C. Hojaij, Pedro Michaluart, Jr, Gregory J. Riggins, Janete M. Cerutti
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-08-2008
• Subjects: Antineoplastic agents; Biological and medical sciences; BRAF; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Cell Line, Tumor; Chemokines, CXC - genetics; Cohort Studies; CST6; CXCL14; Cystatin M; Cystatins - genetics; DHRS3; DNA Mutational Analysis; Endocrinopathies; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic Metastasis; Malignant tumors; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Osteopontin - genetics; Oxidoreductases - genetics; papillary thyroid carcinoma; Pharmacology. Drug treatments; Proto-Oncogene Proteins B-raf - biosynthesis; Proto-Oncogene Proteins B-raf - genetics; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid. Thyroid axis (diseases); Endocrinopathy; Thyroid diseases; Malignant lymphadenopathy; Malignant hemopathy; Malignant tumor; Gene expression profile; Lymph node metastasis; BRAF Gene; Messenger RNA; C-Onc gene; Genetics; Mutation; Papillary thyroid carcinoma; Protooncogene; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-4372

Purpose: To identify papillary thyroid carcinoma (PTC)–associated transcripts, we compared the gene expression profiles of three Serial
Analysis of Gene Expression libraries generated from thyroid tumors and a normal thyroid tissue.
Experimental Design: Selected transcripts were validated in a panel of 57 thyroid tumors using quantitative PCR (qPCR). An independent set of
71 paraffin-embedded sections was used for validation using immunohistochemical analysis. To determine if PTC-associated gene
expression could predict lymph node involvement, a separate cohort of 130 primary PTC (54 metastatic and 76 nonmetastatic)
was investigated. The BRAF V600E mutational status was compared with qPCR data to identify genes that might be regulated by abnormal BRAF/MEK/extracellular
signal-regulated kinase signaling.
Results: We identified and validated new PTC-associated transcripts. Three genes ( CST6, CXCL14 , and DHRS3 ) are strongly associated with PTC. Immunohistochemical analysis of CXCL14 confirmed the qPCR data and showed protein expression in PTC epithelial cells. We also observed that CST6, CXCL14, DHRS3 , and SPP1 were associated with PTC lymph node metastasis, with CST6, CXCL14 , and SPP1 being positively correlated with metastasis and DHRS3 being negatively correlated. Finally, we found a strong correlation between CST6 and CXCL14 expression and BRAF V600E mutational status, suggesting that these genes may be induced subsequently to BRAF activation and therefore may be downstream in the BRAF/MEK/extracellular signal-regulated kinase signaling pathway.
Conclusion: CST6, CXCL14, DHRS3 , and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for PTC therapy.