Genomic Dissection of Hurthle Cell Carcinoma Reveals a Unique Class of Thyroid Malignancy
Genomic Dissection of Hurthle Cell Carcinoma Reveals a Unique Class of Thyroid Malignancy
复制标题
DOI：
10.1210/jc.2012-3539
复制
发表时间：
2013-05-01
影响因子：
5.8
通讯作者：
Chan, Timothy A.
中科院分区：
文献类型：
--
作者：
Ganly, Ian;Ricarte Filho, Julio;Chan, Timothy A.
背景：Hurthle 细胞癌 (HCC) 是一种尚未得到充分研究的癌症，预后不良。目的：我们的目标是阐明 HCC 的基因组基础。设计和设置：我们在一家三级癌症机构中对 HCC 的突变、基因表达谱和拷贝数变化进行了大规模综合分析。方法：使用基于质谱的基因分型来询问 HCC 中的热点点突变。 最常见的甲状腺癌基因：BRAF、RET、NRAS、HRAS、KRAS、PIK3CA、MAP2K1 和 AKT1。此外，还通过 RT-PCR 评估了 RET 和 NTRK1 以及 PAX8/PPAR gamma 和 AKAP9-BRAF 的常见致癌融合。在与突变分析相同的肿瘤组中确定全局拷贝数变化和基因表达谱。结果：我们报告，HCC 的突变、转录和拷贝数谱与乳头状甲状腺癌和滤泡性甲状腺癌不同，表明 HCC 是一种独特的甲状腺恶性肿瘤类型。基因表达的无监督分层聚类显示 3 组 Hurthle 肿瘤（Hurthle 细胞腺瘤 [HA]、微创 Hurthle 细胞癌 [HMIN] 和广泛侵袭性 Hurthle 细胞癌 [HWIDE] 分别聚类，HWIDE 和 HA 之间存在显着差异。全局拷贝数分析还表明可能以 HWIDE 和 HA 形式出现的不同肿瘤亚组。 嗯。区分 HA 和 HWIDE 的分子通路包括 PIK3CA-Akt-mTOR 和 Wnt/β-catenin 通路，这可能为此类恶性肿瘤的新靶点提供理论依据。结论：我们的数据提供证据表明，HCC 可能是一种不同于乳头状和滤泡状甲状腺癌的独特甲状腺癌。
Context: Hurthle cell cancer (HCC) is an understudied cancer with poor prognosis.Objective: Our objective was to elucidate the genomic foundations of HCC.Design and Setting: We conducted a large-scale integrated analysis of mutations, gene expression profiles, and copy number alterations in HCC at a single tertiary-care cancer institution.Methods: Mass spectrometry-based genotyping was used to interrogate hot spot point mutations in the most common thyroid oncogenes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, MAP2K1, and AKT1. In addition, common oncogenic fusions of RET and NTRK1 as well as PAX8/PPAR gamma and AKAP9-BRAF were also assessed by RT-PCR. Global copy number changes and gene expression profiles were determined in the same tumor set as the mutational analyses.Results: We report that the mutational, transcriptional, and copy number profiles of HCC were distinct from those of papillary thyroid cancer and follicular thyroid cancer, indicating HCC to be a unique type of thyroid malignancy. Unsupervised hierarchical clustering of gene expression showed the 3 groups of Hurthle tumors (Hurthle cell adenoma [HA], minimally invasive Hurthle cell carcinoma [HMIN], and widely invasive Hurthle cell carcinoma [HWIDE] clustered separately with a marked difference between HWIDE and HA. Global copy number analysis also indicated distinct subgroups of tumors that may arise as HWIDE and HMIN. Molecular pathways that differentiate HA from HWIDE included the PIK3CA-Akt-mTOR and Wnt/beta-catenin pathways, potentially providing a rationale for new targets for this type of malignancy.Conclusions: Our data provide evidence that HCC may be a unique thyroid cancer distinct from papillary and follicular thyroid cancer.