Does the 3-gene assay accurately distinguish benign from malignant thyroid neoplasms?

ArticleinCancer 113(5):930-5 · September 2008with5 Reads
DOI: 10.1002/cncr.23703 · Source: PubMed
A 3-gene (PCSK2, PLAB, CCND2) assay has been reported to have high accuracy for distinguishing benign from malignant thyroid tumors that are often indeterminate on fine-needle aspiration (FNA) biopsy. The aim of the current study was to determine the diagnostic accuracy of the 3-gene assay in thyroid tissue and in FNA biopsy for distinguishing benign from malignant thyroid neoplasms. The messenger ribonucleic acid (mRNA) expression level of 3 genes (PCSK2, PLAB, CCND2) was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction in 261 frozen thyroid tissue samples (138 benign and 123 malignant), and prospectively, in 144 clinical thyroid FNA samples. To determine the diagnostic accuracy of the 3-gene assay, the area under the curve (AUC) of the receiver operating characteristic curve for each gene individually and in combination was determined. PCSK2 and CCND2 mRNA expression levels were found to be significantly different between benign and malignant thyroid tissue samples (P < .0001 and P = .0007, respectively), but PLAB mRNA expression level was not (P = .099). In the thyroid tissue samples, the AUC was 0.67 for PCSK2 and 0.62 for CCND2. In the thyroid FNA samples, PCSK2 and CCND2 were significantly differentially expressed between benign and malignant samples (P = .039 and P = .023, respectively). The AUC was 0.59 for PCSK2 and 0.61 for CCND2. Although PCSK2 and CCND2 were significantly differentially expressed between benign and malignant thyroid tumors both in tissue and in FNA samples, the diagnostic accuracy of the 3-gene assay was low. These findings demonstrate that it is essential for studies to validate the diagnostic accuracy and clinical utility of emerging candidate diagnostic thyroid cancer markers if they are to be translated into clinically useful markers for making patient care decisions.
    • "The first data on the association of PCs with cancer were published in 1987 [5]. Since then, numerous studies analyzed the expression of PCs in cancer and the correlations between the PC expression levels and cancer properties using various experimental approaches6789101112131415161718192021. Overall, the data obtained demonstrated altered levels of PC mRNAs in cancer. "
    [Show abstract] [Hide abstract] ABSTRACT: Proprotein convertases (PCs) is a protein family which includes nine highly specific subtilisin-like serine endopeptidases in mammals. The system of PCs is involved in carcinogenesis and levels of PC mRNAs alter in cancer, which suggests expression status of PCs as a possible marker for cancer typing and prognosis. The goal of this work was to assess the information value of expression profiling of PC genes. Quantitative polymerase chain reaction was used for the first time to analyze mRNA levels of all PC genes as well as matrix metalloproteinase genes MMP2 and MMP14, which are substrates of PCs, in 30 matched pairs of samples of human lung cancer tumor and adjacent tissues without pathology. Significant changes in the expression of PCs have been revealed in tumor tissues: increased FURIN mRNA level (p<0.00005) and decreased mRNA levels of PCSK2 (p<0.007), PCSK5 (p<0.0002), PCSK7 (p<0.002), PCSK9 (p<0.00008), and MBTPS1 (p<0.00004) as well as a tendency to increase in the level of PCSK1 mRNA. Four distinct groups of samples have been identified by cluster analysis of the expression patterns of PC genes in tumor vs. normal tissue. Three of these groups covering 80% of samples feature a strong elevation in the expression of a single gene in cancer: FURIN, PCSK1, or PCSK6. Thus, the changes in the expression of PC genes have a limited number of scenarios, which may reflect different pathways of tumor development and cryptic features of tumors. This finding allows to consider the mRNAs of PC genes as potentially important tumor markers.
    Full-text · Article · Feb 2013
    • "Unfortunately, about 30% of FNAs are indeterminate and often require a diagnostic thyroidectomy to establish the diagnosis on permanent histological examination. Only 20% of diagnostic thyroidectomies in patients with indeterminate FNA cytology demonstrates malignant lesions on permanent histology, and these patients often require a completion thyroidectomy [5]. Therefore, because of this obvious limitation of FNA cytology in the preoperative diagnosis, there is a clinical need for reliable preoperative molecular markers to distinguish benign from malignant thyroid nodules. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Thyroid nodules with indeterminate cytological features on fine needle aspiration (FNA) cytology have a 20% risk of thyroid cancer. The aim of the current study was to determine the diagnostic utility of an 8-gene assay to distinguish benign from malignant thyroid neoplasm. Methods The mRNA expression level of 9 genes (KIT, SYNGR2, C21orf4, Hs.296031, DDI2, CDH1, LSM7, TC1, NATH) was analysed by quantitative PCR (q-PCR) in 93 FNA cytological samples. To evaluate the diagnostic utility of all the genes analysed, we assessed the area under the curve (AUC) for each gene individually and in combination. BRAF exon 15 status was determined by pyrosequencing. An 8-gene computational model (Neural Network Bayesian Classifier) was built and a multiple-variable analysis was then performed to assess the correlation between the markers. Results The AUC for each significant marker ranged between 0.625 and 0.900, thus all the significant markers, alone and in combination, can be used to distinguish between malignant and benign FNA samples. The classifier made up of KIT, CDH1, LSM7, C21orf4, DDI2, TC1, Hs.296031 and BRAF had a predictive power of 88.8%. It proved to be useful for risk stratification of the most critical cytological group of the indeterminate lesions for which there is the greatest need of accurate diagnostic markers. Conclusion The genetic classification obtained with this model is highly accurate at differentiating malignant from benign thyroid lesions and might be a useful adjunct in the preoperative management of patients with thyroid nodules.
    Full-text · Article · Sep 2012
    • "Weber et al. proposed that a combination of those three genes allowed the accurate molecular classification of FTC versus FTA with a high specificity and sensitivity. However, Shibru et al. were unable to confirm the diagnostic accuracy of the 3-gene assay either in frozen tissue or in FNAs [16]. The difference is likely attributed to the difference in types of analyzed tissue, as Shibru et al. compared a benign group represented by hyperplastic nodule, FTA, Hürthle cell adenomas (HCAs) with a collective group of thyroid malignancies, including FTC, PTC, follicular variant of PTC, HCC. "
    [Show abstract] [Hide abstract] ABSTRACT: The development of molecular biomarkers (BMs) of follicular thyroid carcinoma is aimed at advancing diagnosis of follicular neoplasm, as histological examination of those tumors does not lend itself to definitive diagnosis of carcinoma. We assessed the relative levels of expression of 6 genes: CCND2, PCSK2, PLAB, RAP2A, TSHR, and IGF-1R in archived thyroid tissue. The quantitative real-time PCR analysis revealed a significant change in 3 genes: PSCK2 (a 22.4-fold decrease, P = 2.81E - 2), PLAB (an 8.3-fold increase, P = 9.81E - 12), and RAP2A (a 6.3-fold increase, P = 9.13E - 10) in carcinoma compared with adenoma. Expression of PCSK2 was equally low, PLAB was equally high, whereas RAP2A expression was significantly higher (25.9-fold, P = 0.039) in microdissected carcinoma cells that have invaded through the thyroid capsule and entered blood vessels than in thyroid tumor cells growing under the capsule. Thus, RAP2A appeared as a unique and worthy of further evaluation candidate BM associated with invasion of thyroid follicular cells.
    Full-text · Article · Oct 2011
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