1 Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea.
2 Department of Pathology, and Seoul National University College of Medicine, Seoul National University Hospital , Seoul, Korea.
Thyroid. 2018 Nov;28(11):1468-1478. doi: 10.1089/thy.2018.0198. Epub 2018 Oct 16.
Among subtypes of follicular variant of papillary thyroid carcinoma (FVPTC), encapsulated FVPTC (EFVPTC) shows more indolent behavior than infiltrative FVPTC (IFVPTC). In particular, noninvasive EFVPTC, now designated as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), tends to have an excellent prognosis. However, it remains unclear whether the molecular pathogenesis or signature of the various forms of FVPTC is different. By massively parallel sequencing analysis, this study comprehensively characterized the transcriptional and mutational landscape of FVPTC and established correlations with phenotypic subtypes.
This study included 48 FVPTCs: 17 NIFTPs, 13 invasive EFVPTCs (I-EFVPTCs), and 18 IFVPTCs. For comparison, 55 classical papillary thyroid carcinomas (cPTCs) harboring a BRAF mutation, six follicular adenomas (FAs), and 15 minimally invasive follicular thyroid carcinomas (miFTCs) with RAS mutations were also included.
In NIFTP, the BRAF mutation was not found, but RAS and other alterations were present in 64.7% and 17.6% of cases, respectively. However, in I-EFVPTC and IFVPTC, the proportions of BRAF mutation (38.5% and 38.9%, respectively) and of RAS mutations (38.5% and 38.9%, respectively) or other alterations (15.4% and 16.7%, respectively) were similar. On a molecular level, RAS-mutated FVPTCs were all RAS-like except for one IFVPTC case. Transcriptomic profiles of NIFTP, I-EFVPTC, and FA/miFTC were comparable, although the profile of RAS-mutated IFVPTC was altered to activate molecular pathways involved in cell adhesion and invasion. Interestingly, 80% of BRAF-mutated I-EFVPTCs were also classified as RAS-like, whereas all BRAF-mutated IFVPTCs were BRAF-like and indistinguishable from cPTC. Molecular pathways associated with cell adhesion and invasion were also differentially activated in BRAF-mutated IFVPTC.
Molecular profiles of NIFTP and I-EFVPTC may be shared with FA/miFTC, while IFVPTC seems to be associated with a similar profile as cPTC. Activation of cell adhesion and invasion pathways may play a key role in the development of invasive phenotypes of FVPTC.
在滤泡型甲状腺癌（FVPTC）的亚型中，包膜型滤泡型甲状腺癌（EFVPTC）的行为比浸润型滤泡型甲状腺癌（IFVPTC）更为惰性。特别是无侵袭性 EFVPTC，现在被指定为无侵袭性滤泡性甲状腺肿瘤伴乳头状核特征（NIFTP），往往具有极好的预后。然而，目前尚不清楚各种 FVPTC 的分子发病机制或特征是否不同。通过大规模平行测序分析，本研究全面描述了 FVPTC 的转录组和突变景观，并与表型亚型建立了相关性。
本研究纳入 48 例 FVPTC：17 例 NIFTP，13 例浸润性 EFVPTC（I-EFVPTC）和 18 例 IFVPTC。为了比较，还纳入了 55 例含有 BRAF 突变的经典甲状腺乳头状癌（cPTC）、6 例滤泡性腺瘤（FA）和 15 例具有 RAS 突变的微小浸润性滤泡性甲状腺癌（miFTC）。
在 NIFTP 中未发现 BRAF 突变，但在 64.7%和 17.6%的病例中分别存在 RAS 和其他改变。然而，在 I-EFVPTC 和 IFVPTC 中，BRAF 突变的比例（分别为 38.5%和 38.9%）和 RAS 突变或其他改变的比例（分别为 38.5%和 38.9%）相似。在分子水平上，除了 1 例 IFVPTC 外，RAS 突变的 FVPTC 均为 RAS 样。NIFTP、I-EFVPTC 和 FA/miFTC 的转录组谱相似，尽管 RAS 突变的 IFVPTC 的转录组谱发生改变，激活了参与细胞黏附侵袭的分子通路。有趣的是，80%的 BRAF 突变的 I-EFVPTC 也被归类为 RAS 样，而所有的 BRAF 突变的 IFVPTC 均为 BRAF 样，与 cPTC 无法区分。BRAF 突变的 IFVPTC 中也激活了与细胞黏附和侵袭相关的分子通路。
NIFTP 和 I-EFVPTC 的分子谱可能与 FA/miFTC 共享，而 IFVPTC 似乎与 cPTC 具有相似的特征。细胞黏附和侵袭通路的激活可能在 FVPTC 侵袭表型的发展中起关键作用。
