Identification of borderline thyroid tumors by gene expression array analysis.
BACKGROUND
A subset of follicular lesions of the thyroid is encapsulated similar to follicular adenomas but with partial nuclear features suggestive of papillary thyroid carcinoma (PTC), raising the possibility of biologically borderline tumors.


METHODS
Gene expression profiling and advanced significance analyses were performed on 50 histologically unequivocal benign and malignant tumors, and a list of 61 differentially expressed genes was generated. By using this 61-gene list, unsupervised hierarchical and K-means cluster analyses were performed on 40 additional tumors, including 15 histologically borderline tumors, 11 benign tumors, and 14 PTCs.


RESULTS
Analysis revealed 3 distinct tumor groups-benign, malignant, and intermediate. Tumors in the intermediate group (n = 15) were mostly histologic borderline tumors and had an expression profile overlapping with the benign and malignant groups. Twenty-seven genes were expressed differentially between the benign and intermediate groups, including the cyclic AMP response element-binding protein/p300-interactivator with glutamic acid/aspartic acid-rich carboxy-terminal domain 1 or CITED1 gene and the fibroblast growth factor receptor 2 or FGFR2 gene. Fourteen genes were expressed differentially between the intermediate group and malignant tumors, notably overexpression of the met proto-oncogene and of the high-mobility group adenine/thymine-hook 2 or HMGA2 gene in malignancies. Mutations of the v-raf murine sarcoma viral oncogene homolog B1 or BRAF gene were identified in 4 of 14 malignant tumors but not in benign or intermediate tumors. Patients who had either histologically or molecularly borderline tumors did not have metastasis or recurrences.


CONCLUSIONS
Gene expression profiling supported the finding that encapsulated thyroid follicular lesions with partial nuclear features of PTC are biologically borderline tumors that are distinct molecularly from benign and malignant tumors.
Arora
Nimmi
N
Department of Surgery, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, New York 10065, USA. nsk2002@med.cornell.edu
Scognamiglio
Theresa
T
Lubitz
Carrie C
CC
Moo
Tracy A
TA
Kato
Meredith A
MA
Zhu
Baixin
B
Zarnegar
Rasa
R
Chen
Yao-Tseng
YT
Fahey
Thomas J
TJ
D018265:Carcinoma, Papillary, Follicular / Q000175:diagnosis / Q000235:genetics; D016000:Cluster Analysis; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013964:Thyroid Neoplasms / Q000175:diagnosis* / Q000235:genetics*
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D048493:Proto-Oncogene Proteins B-raf