Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
Cancer. 2010 Jun 15;116(12):2974-83. doi: 10.1002/cncr.25061.
The follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common histotype among papillary thyroid cancers (PTCs). Although the prognosis of FVPTC is similar to the conventional phenotype, differential diagnostic difficulties may not be uncommon with other follicular thyroid neoplasms, and little is known about their genetic alterations. Defining these alterations may lead to the identification of diagnostic and biologic markers.
In this study, the authors evaluated genetic alterations and downstream-activated signals of the Ras/Raf-mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene (Akt) (PI3K/Akt) signaling pathways in 30 FVPTC tissue specimens. Tumors and matched normal thyroid samples were tested for RAS, for the v-raf murine sarcoma viral oncogene (BRAF) substitution of valine (V) for glutamate (E) at codon 600 (the V600E mutation), for phosphatase and tensin homolog (PTEN), for catalytic PI3k p110 subunit alpha (PIK3CA), for AKT, and for the presence of rearranged during transfection (ret) proto-oncogene/PTC (RET-PTC) and paired box-8 (PAX8)/peroxisome proliferator-activated receptor gamma (PPARgamma) fusion protein (PAX8-PPARgamma) rearrangements by direct sequencing and reverse transcriptase-polymerases chain reaction analyses, respectively. Western blot analysis was used to assess the effects of these gene abnormalities on the activation of the 2 pathways.
Genetic alterations were identified in 70% of FVPTCs. Activation of the MAPK and PI3K pathways was observed in 74% and 22% of tumors, respectively. The alterations that were identified in the genes of the 2 pathways were mutually exclusive. Chromosomal RET-PTC and PAX8-PPARgamma rearrangements were observed in 20% and 17% of tumors, respectively. It was noteworthy that some FVPTCs with RET-PTC had the coactivation of both pathways.
RET-PTC and PAX8-PPARgamma rearrangements and mutations of the neuroblastoma RAS viral oncogene homolog N-RAS at codon 61 were the most common genetic alterations in FVPTCs. Activation of the MAPK pathway was a frequent event in FVPTCs, and the PI3K signaling pathway could be coactivated in RET-PTC tumors. These findings may have important therapeutic implication in patients with FVPTC.
滤泡状甲状腺癌（FVPTC）是甲状腺癌（PTC）中第二常见的组织学类型。虽然 FVPTC 的预后与常规表型相似，但与其他滤泡性甲状腺肿瘤的鉴别诊断可能并不少见，而且对其遗传改变知之甚少。明确这些改变可能有助于识别诊断和生物学标志物。
在这项研究中，作者评估了 30 例 FVPTC 组织标本中 Ras/Raf-丝裂原活化蛋白激酶（MAPK）和磷酸肌醇 3-激酶（PI3K）/v-akt 鼠胸腺瘤病毒癌基因（Akt）（PI3K/Akt）信号通路的遗传改变和下游激活信号。检测肿瘤和匹配的正常甲状腺样本中的 RAS、v-raf 鼠肉瘤病毒癌基因（BRAF）的谷氨酸（E）取代缬氨酸（V）的密码子 600（V600E 突变）、磷酸酶和张力蛋白同源物（PTEN）、催化 PI3K p110 亚单位α（PIK3CA）、AKT，以及转染过程中重排（RET）原癌基因/PTC（RET-PTC）和配对盒 8（PAX8）/过氧化物酶体增殖物激活受体γ（PPARγ）融合蛋白（PAX8-PPARγ）重排通过直接测序和逆转录聚合酶链反应分析分别进行。Western blot 分析用于评估这些基因异常对 2 条通路激活的影响。
在 70%的 FVPTC 中发现了遗传改变。MAPK 和 PI3K 通路的激活分别在 74%和 22%的肿瘤中观察到。两条通路基因中的改变是相互排斥的。染色体 RET-PTC 和 PAX8-PPARγ 重排在 20%和 17%的肿瘤中分别观察到。值得注意的是，一些具有 RET-PTC 的 FVPTC 同时激活了这两条通路。
RET-PTC 和 PAX8-PPARγ 重排以及神经母细胞瘤 RAS 病毒癌基因同源物 N-RAS 密码子 61 的突变是 FVPTC 中最常见的遗传改变。MAPK 通路的激活在 FVPTC 中是一个常见事件，PI3K 信号通路可在 RET-PTC 肿瘤中被共激活。这些发现可能对 FVPTC 患者的治疗具有重要意义。
