Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Clin Endocrinol Metab. 2013 Mar;98(3):E558-66. doi: 10.1210/jc.2012-3113. Epub 2013 Jan 23.
Fine-needle aspiration (FNA) is the best diagnostic tool for preoperative evaluation of thyroid nodules but is often inconclusive as a guide for surgical management.
Our hypothesis was that thyroid tumor subtypes may show characteristic DNA copy number variation (CNV) patterns, which may further improve the preoperative classification.
Our study cohorts included benign follicular adenomas (FAs), classic papillary thyroid carcinomas (PTCs), and follicular variant PTCs (FVPTCs), the three subtypes most commonly associated with inconclusive preoperative cytopathology.
Tissue and FNA samples were obtained at an academic tertiary referral center.
Cases were identified that underwent partial or complete thyroidectomy for malignant or indeterminate thyroid lesions between 2000 and 2008 and had adequate snap-frozen tissue.
Pairs of tumor tissue and matching normal thyroid tissue-derived DNA were compared using 550K single-nucleotide polymorphism arrays.
Statistically significant differences in CNV patterns between tumor subtypes were identified.
Segmental amplifications in chromosomes (Ch) 7 and 12 were more common in FAs than in PTCs or FVPTCs. Additionally, a subset of FAs and FVPTCs showed deletions in Ch22. We identified the 5 CNV-associated genes best at discriminating between FAs and PTCs/FVPTCs, which correctly classified 90% of cases. These 5 Ch12 genes were validated by quantitative genomic PCR and gene expression array analyses on the same patient cohort. The 5-gene signature was then successfully validated against an independent test cohort of benign and malignant tumor samples. Finally, we performed a feasibility study on matched FA-derived intraoperative FNA samples and were able to correctly identify FAs harboring the Ch12 amplification signature, whereas FAs without amplification showed a normal Ch12 signature.
Thyroid tumor subtypes possess characteristic genomic profiles that may further our understanding of structural genetic changes in thyroid tumor subtypes and may lead to the development of new diagnostic biomarkers in FNA samples.
细针穿刺（FNA）是术前评估甲状腺结节的最佳诊断工具，但作为手术管理的指导往往不够明确。
我们的假设是，甲状腺肿瘤亚型可能表现出特征性的 DNA 拷贝数变异（CNV）模式，这可能进一步提高术前分类的准确性。
我们的研究队列包括良性滤泡性腺瘤（FA）、经典乳头状甲状腺癌（PTC）和滤泡状变异型 PTC（FVPTC），这三种亚型与术前细胞学检查不确定的情况最相关。
组织和 FNA 样本取自学术性三级转诊中心。
我们确定了 2000 年至 2008 年间因恶性或不确定的甲状腺病变而行部分或全甲状腺切除术的患者，且这些患者有足够的冷冻组织。
使用 550K 单核苷酸多态性阵列比较肿瘤组织和匹配的正常甲状腺组织衍生的 DNA。
鉴定出肿瘤亚型之间 CNV 模式的统计学显著差异。
FA 中常见染色体（Ch）7 和 12 的片段扩增，而在 PTC 或 FVPTC 中则不常见。此外，一部分 FA 和 FVPTC 显示 Ch22 缺失。我们确定了最好区分 FA 和 PTC/FVPTC 的 5 个与 CNV 相关的基因，这些基因正确分类了 90%的病例。这些 Ch12 基因在相同患者队列的定量基因组 PCR 和基因表达阵列分析中得到验证。5 基因标志物随后在良性和恶性肿瘤样本的独立测试队列中成功验证。最后，我们对匹配的 FA 衍生的术中 FNA 样本进行了可行性研究，能够正确识别携带 Ch12 扩增特征的 FA，而没有扩增的 FA 则显示正常的 Ch12 特征。
甲状腺肿瘤亚型具有特征性的基因组特征，这可能进一步加深我们对甲状腺肿瘤亚型结构遗传变化的理解，并可能导致新的 FNA 样本诊断生物标志物的开发。
