Diagnostic and prognostic value of cell-cycle regulatory genes in malignant thyroid neoplasms.
BACKGROUND
Approximately 30% of patients with thyroid nodules have indeterminate or suspicious fine-needle aspiration (FNA) biopsy results. Because their risk of cancer is approximately 20%, these patients undergo thyroidectomy. We hypothesized that genes that regulate cell-cycle progression would be differentially expressed in malignant versus benign thyroid nodules and could serve as diagnostic markers and markers of disease aggressiveness.


METHODS
We used a cDNA array with 96 cell-cycle regulatory genes to identify differentially expressed genes in pooled benign versus malignant thyroid neoplasms. Genes up- or down-regulated by more than 2-fold in malignant thyroid neoplasms were further evaluated by real-time quantitative polymerase chain reaction (PCR) in 95 patients with hyperplastic nodules (n = 19), follicular adenoma (n = 19), follicular thyroid cancer (n = 19), the follicular variant of papillary thyroid cancer (n = 19), and papillary thyroid cancer (n = 19).


RESULTS
cDNA array analysis showed that cyclin B1, MCM5, MCM7, RAD9, ubiquitin C, CDK6, SKP2, and APAF1 were up-regulated in malignant thyroid neoplasms. Real-time quantitative PCR showed that MCM5, MCM7, and RAD9 mRNA expression were significantly higher in malignant than in benign thyroid neoplasms (< or = 0.0012). The combined use of MCM5, MCM7, and RAD9 mRNA expression had a sensitivity of 98.2% and a specificity of 65.7%. The level of MCM7 mRNA expression was higher in T4 than in T1, T2, and T3 differentiated thyroid cancers (P < 0.0127).


CONCLUSIONS
MCM5, MCM7, and RAD9 are overexpressed in malignant thyroid neoplasms of follicular cell origin. These genes may be useful markers of malignant thyroid neoplasms as an adjunct to FNA biopsy. MCM7 mRNA expression is higher in locally invasive differentiated thyroid cancer.
Kebebew
Electron
E
San Francisco Comprehensive Cancer Center, University of California, San Francisco, CA 94143-1674, USA. kebebew@surgery.ucsf.edu
Peng
Miao
M
Reiff
Emily
E
Duh
Quan-Yang
QY
Clark
Orlo H
OH
McMillan
Alex
A
D018263:Adenocarcinoma, Follicular / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000235:genetics*; D044963:Biopsy, Fine-Needle; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D064168:Minichromosome Maintenance Complex Component 7; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011379:Prognosis; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D013965:Thyroidectomy
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C489423:MCM5 protein, human; D009687:Nuclear Proteins; C069930:rad9 protein; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7