Gene expression profiling of papillary thyroid carcinoma identifies transcripts correlated with BRAF mutational status and lymph node metastasis.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
CST6, CXCL14, DHRS3, and SPP1 may play a role in PTC pathogenesis and progression and are possible molecular targets for PTC therapy.
Oler
Gisele
G
Division of Genetics, Federal University of São Paulo, Sãp Paulo, Brazil.
Camacho
Cléber P
CP
Hojaij
Flávio C
FC
Michaluart
Pedro
P
Riggins
Gregory J
GJ
Cerutti
Janete M
JM
D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019743:Chemokines, CXC / Q000235:genetics*; D015331:Cohort Studies; D055332:Cystatin M; D015891:Cystatins / Q000235:genetics*; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D053495:Osteopontin / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000096:biosynthesis* / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism*
C525104:CST6 protein, human; C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D055332:Cystatin M; D015891:Cystatins; C506895:SPP1 protein, human; D053495:Osteopontin; D010088:Oxidoreductases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases