Baixin Zhu

Discrimination of Benign and Malignant Thyroid Nodules by Molecular Profiling

Background:The evaluation of thyroid nodules by fine-needle aspiration has been the standard for almost 30 years, despite significant shortcomings in sensitivity and specificity. Recent data from our laboratory have suggested that molecular profiling permits the discrimination of specific types of thyroid nodules. These studies were undertaken to determine whether molecular profiling can discriminate between benign and malignant thyroid nodules with the necessary sensitivity and specificity required of a screening test. Methods:Molecular profiles of 11 papillary thyroid carcinomas, 13 follicular variant of papillary thyroid carcinomas, 9 follicular thyroid carcinomas, and 26 benign tumors (follicular adenomas and hyperplastic nodules) were analyzed by oligonucleotide microarray analysis. A gene list was created based on 45 samples. Seventeen samples were then added to the analysis as unknowns. A hierarchical clustering analysis was performed on all 62 samples to examine the groups for potential differences and the ability of the gene list to distinguish tumor types. Results:Cluster analysis of all 62 samples produced 2 distinct groups, 1 containing the carcinomas and 1 containing the benign lesions. The sensitivity for a diagnosis of cancer was 91.7% with a specificity of 96.2% (3 follicular variant of papillary thyroid carcinomas clustered with the benign lesions). The cancer gene profiles contained both known cancer-associated genes (MET, galectin-3) and previously unidentified genes. Conclusions:Molecular profiling readily distinguishes between benign and malignant thyroid tumors with excellent sensitivity and specificity. Elucidated genes may provide insight into the molecular pathogenesis of thyroid cancer. Gene profiling may significantly enhance the evaluation of thyroid nodules in the future.

Do Benign Thyroid Nodules Have Malignant Potential? An Evidence-Based Review

BackgroundBenign thyroid tumors account for most nodular thyroid disease. Determination of whether a thyroid nodule is benign or malignant is a major clinical dilemma and underlies the decision to proceed to surgery in many patients. Although the accuracy of thyroid nodule fine-needle aspiration (FNA) has reduced the need for surgery over the years, questions regarding how to follow FNA-designated benign nodules remain unresolved. This is true at least in part because of uncertainty over whether some benign nodules harbor malignant potential.MethodsAn evidence-based review of recent clinical, pathologic, and molecular data is presented. A summary of data and observations from our own experience is also provided.ResultsReview of our recent 10-year experience indicates that 2% of thyroid malignancies arise within a preexisting benign thyroid nodule. In addition, both cytologic and molecular tumor markers, including Gal-3, CITED1, HBME-1, Ras, RET/PTC, and PAX8/PPARγ, have been identified in some histopathologically classified benign nodules. Gene expression profiling suggests that follicular adenomas and Hürthle cell adenomas have similarities to both benign and malignant tumors, suggesting that some of these tumors are premalignant. In addition, 10% of surgically excised follicular tumors are encapsulated follicular lesions with nuclear atypia, which have been termed “well-differentiated tumors of uncertain malignant potential.” The data available suggest that these tumors could be precursors to carcinoma.ConclusionSome benign thyroid nodules have malignant potential. Further molecular testing of these tumors can shed light on the pathogenesis of early malignant transformation.

Identification of borderline thyroid tumors by gene expression array analysis.

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.

Selenium Decreases Thyroid Cancer Cell Growth by Increasing Expression of GADD153 and GADD34

Selenium (Se) supplementation is reported to decrease the incidence and total mortality of cancer. Whereas in vitro and in vivo studies have shown a decrease in prostate, lung, and liver cancers, this has not been shown in thyroid cancer. ARO (anaplastic), NPA (BRAF positive papillary), WRO (BRAF negative papillary), and FRO (follicular) cells treated with 150 μM seleno-l-methionine (SM) were assessed for viability at 24, 48, and 72 h. Treated FRO cells were examined for cell cycle using flow cytometry, for apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and for gene expression using microarray. Genes identified as upregulated were confirmed by real-time PCR (RT-PCR) and proteins by Western blot analysis. SM treatment significantly decreased the proliferation of all cell lines. TUNEL assay showed no evidence of apoptosis, and flow cytometry showed a significant cell-cycle arrest in S (271% increase, P= 0.006) and G2/M (61% increase, P= 0.002) compared to control. Microarray revealed 21 differentially expressed genes with greater than twofold change. A relative overexpression of growth arrest and DNA damage inducible (GADD)34 and GADD153 in treated cells was confirmed with RT-PCR and Western blot. SM inhibits thyroid cancer cell proliferation through a time dependent upregulation of the GADD family of genes and arrest in S and G2/M phases of the cell cycle. This is the first report of selenium induced inhibition of thyroid cancer cell growth.