Abstract 2159: Genomic characterization of benign and malignant thyroid tumors
Authors: Liu Yan , Cope Leslie , Sun Wenyue , Wang Yongchun , Prasad Nijaguna , Sangenario Lauren , Talbot Kristen , Westra William H. , Califano Joseph A. , Zeiger Martha A. , Umbricht Christopher B. 
Published: February 2011

Background: Thyroid cancer cells typically harbor multiple genomic aberrations that drive malignant transformation. The goal of this study was to identify novel genetic markers to improve preoperative discrimination between benign and malignant thyroid neoplasms.

Methods: Using Illumina HumanHap550 BeadChip with 561,446 single-nucleotide polymorphism (SNP) mark¬ers, we estimated copy number (CN) across the genome on 39 thyroid tumors with matched normal tissue, which included 14 benign tumors (follicular adenomas, FAs) and 25 malignant tumors (13 follicular variant papillary thyroid cancers, FVPTCs, and 12 papillary thyroid cancers, PTCs). The Cir¬cu¬lar Binary Seg¬men¬ta¬tion (CBS) algo¬rithm was applied to calculate copy number variation (CNV) based on Log R Ratio (LRR) values. Loss of heterozygosity (LOH) analysis was performed by using LOH Score plug-in in BeadStudio program. Within the regions showing CNV, candidate genes were further examined by real-time PCR.

Results: The comprehensive genetic profile of 39 thyroid tumors was defined, and tumor -specific somatic change assessed using matched normal thyroid tissue as reference. With strict control of the false discovery rate, significant alterations averaged 32 CNVs in benign FAs, and 8 in malignant thyroid cancer (PTCs and FVPTCs), including 17 gains in FAs and 3 gains in cancers, and 2.9 losses in FAs and 4.4 losses in cancers. Additionally, an average of 12 copy-neutral LOHs per FA and 1 LOH per cancer were detected. Among the CNVs, we found 60 focal alterations that were specific either for benign FAs, or for thyroid cancers. We used empirical Bayes modified ANOVA to identify genes for which copy number was associated with tumor type. Increases in copy number on chromosome 12 were much more common in FAs than in cancers. GDF3, a candidate gene located in 12p13.31, was further validated by quantitative real time PCR, which showed results consistent with our SNP array results. Overall, follicular adenomas showed considerably higher levels of copy number variation than the two malignant tumor subtypes studied, i.e. PTCs and FVPTCs.

Conclusions: Benign and malignant thyroid tumors may possess characteristic and distinguishable genomic profiles. The genetic changes identified in this study may allow the development of biomarkers for differentiation of benign and malignant thyroid nodules.

In the next phase of this study, we will perform a transcriptome-wide expression analysis on the same tissue sample set used for the SNP array study, and perform an integrated analysis combining DNA genetic alterations and differential gene expression to further refine the identification of candidate molecular changes that may be used in differentiating benign from malignant thyroid lesions.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2159.