EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)

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  摘要
  滤泡性甲状腺肿瘤主要呈滤泡生长模式,常可见RAS基因突变而非BRAF基因突变。随着分子检测技术的进步,一些新型RAS类突变被发现。然而,这些突变的临床意义尚不明确。我们使用Sanger测序法对201例具有滤泡结构的甲状腺肿瘤的BRAF,NRAS,HRAS,KRAS,EZH1,EIFIAX和TERT基因突变进行测序,并研究这些突变的发生率以及其对临床的影响。这些肿瘤包括滤泡型腺瘤(n=40)、Hürthle细胞腺瘤(n=54)、具有乳头状核特征的非浸润性滤泡性甲状腺肿瘤(n=10)、滤泡性甲状腺癌(n=40)、Hürthle细胞癌(n=10)、发生于高分化滤泡性肿瘤的低分化甲状腺癌(n=7)和120例经典乳头状癌。EZH1突变的2个热点仅见于RAS阴性的滤泡结构的肿瘤。EZH1突变可见于3%的滤泡型腺瘤、20%的Hürthle细胞腺瘤以及1例微浸润型Hürthle细胞癌中。在已报道的文献中,伴EZH1突变的甲状腺肿瘤大多为良性,或者为微浸润或无浸润的癌。EIF1AX突变见于1例滤泡腺瘤中。我们确认了RAS突变和BRAF K601E突变可见于良性、交界性或恶性滤泡性肿瘤中。所有滤泡性肿瘤中未见BRAF V600E突变。本研究还确认了在高风险甲状腺癌中存在TERT启动子突变。这些遗传标志物可用于甲状腺结节的诊断和风险分级。
  前言
  甲状腺主要由单层滤泡细胞排列而成的甲状腺滤泡构成,滤泡腔内含胶质。滤泡结构的甲状腺肿瘤来源于滤泡细胞,包括滤泡型腺瘤、Hürthle细胞腺瘤、具有乳头状细胞核特征的非浸润性滤泡性甲状腺肿瘤(NIFTP)、滤泡型甲状腺乳头状癌(PTC)、滤泡性甲状腺癌(FTP)以及Hürthle细胞癌[1]。在2017版WHO甲状腺肿瘤分类中,NIFTP被定为“国际疾病分类肿瘤生物学行为代码1”以说明其非特定的、交界性的或不确定的生物学行为[1]。低分化甲状腺癌(PDTC)可以来源于先前存在的高分化滤泡型肿瘤[1]。由于这些肿瘤存在重叠的形态学特征和较差的观察者间一致性,有时病理诊断非常困难。[2-4]
  滤泡性生长模式为主的甲状腺肿瘤常见RAS突变和PPARG重排[1]。具有乳头结构的PTCs可见BRAF V600E突变和RET重排[1]。BRAF、RAS、RET和PPARG突变在甲状腺癌中是相互排斥。基于71个基因标签,癌症基因组图谱(TCGA)研究将PTCs分为BRAF V600E样肿瘤和RAS样肿瘤两大类。RAS样PTCs与滤泡样亚型和低复发风险显著相关。这些肿瘤中可见非V600E的BRAF点突变、NRAS、HRAS、KRAS和EIF1AX基因的点突变,还可见PPARG、FGFR2和THADA基因重排[5]。TERT启动子突变与侵袭性甲状腺癌显著相关[5-7]。我们先前的研究表明,RAS、EZH1和EIF1AX突变可能是滤泡型腺瘤发展的早期基因事件[8]。然而,在多种滤泡性甲状腺肿瘤的RAS样突变中,近期发现的EIF1AX和EZH1突变的发生率及其临床应用尚未阐明。
  因此,本研究的目的即是确定RAS样突变和TERT启动子突变在良性、交界性和恶性的具有滤泡结构的甲状腺肿瘤中的发生率和临床意义。
  结果
  201例滤泡结构的甲状腺肿瘤的分子谱
  整体上,体细胞突变可见于93/201例(46.3%)滤泡性甲状腺肿瘤中。基于组织学亚型的突变特征谱见表1。NRAS、HRAS、KRAS、EIF1AX、BRAF、EZH1和TERT基因在滤泡性甲状腺肿瘤中的突变率分别为21.9%、9.5%、4.0%、0.5%、3.0%、6.5%和2.5%(图1)。由于相互排斥,这些突变除TERT启动子突变之外均不会共存于同一病例(图2)。
  35.3%的病例可见所有三种RAS基因的点突变。恶性肿瘤的总体RAS基因突变率(42.1%)显著高于良性肿瘤(23.4%,P=0.44)。然而,针对突变亚型进行特异性分析,发现良性和恶性肿瘤的突变率之间没有显著差异。
  所有BRAF突变阳性的病例可见p.K601E突变,未见BRAF V600E。3/5的TERT启动子突变病例同时伴RAS突变(图1)。
  基于组织学分类的分子基因型信息总结于图2。代表性的组织学图像见图3。RAS突变可见于13/40例(32.5%)滤泡型腺瘤、18/40例(45%)FTCs、17%的Hürthle细胞腺瘤、20%的Hürthle细胞癌、50%的NIFTP和57%的PDTC中。EZH1突变可见于3%的滤泡型腺瘤、20%的Hürthle细胞腺瘤和10%的Hürthle细胞癌中。FTC和Hürthle细胞癌被分为三种组织学类型:微浸润型、包裹性血管浸润型和广泛浸润型(表2)。BRAF V600E和EZH1突变仅见于微浸润型。
  120例经典PTCs的分子谱
  所有BRAF突变阳性的病例可见V600E突变。未见RAS、EIF1AX或EZH1基因突变。2/120例(1.7%)经典PTCs可见TERT启动子突变(表1)。
  甲状腺肿瘤EZH1突变的文献综述
  5篇文献报道了甲状腺病变中的EZH1突变(表3)[5,8,14-16]。包括本研究在内的文献显示,在甲状腺肿瘤中发现的EZH1突变类型包括Q571R、Y642F和M349L,分别占82%、17%和1%(图4)。EZH1突变主要见于良性甲状腺疾病(9.1%的结节性增生,5.9%的传统滤泡型腺瘤,23.1%的Hürthle细胞腺瘤,以及26.6%的自主功能性腺癌),但罕见于恶性肿瘤(表3)。在77例伴EZH1突变的甲状腺肿瘤中,71例(92%)为良性,3例(4%)为微浸润FTC,1例(1%)为微浸润Hürthle细胞癌[8,14-16]。其余2例为滤泡性PTC,由TCGA研究报道[5]。包括本研究在内的6组数据的统计显示,整体EZH1突变率在良性(n=524)、交界性(NIFTP,n=50)和恶性(n=894)中分别为13.5%,0%和0.7%(图5)。良性组(13.5%,95%置信区间=10.6%-17.1%)与恶性组(0.7%,95%置信区间=0.2%-1.5%)之间存在显著差异(P<0.001)。
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
  Figure 1
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
  Fig. 1. The landscape of functional somatic mutations in NRAS, HRAS, KRAS, EIF1AX, BRAF, EZH1, and TERT genes detected in follicular-patterned thyroid tumors (n=201) and classic papillary thyroid carcinoma (n=120). The frequency of mutation is indicated in the left axis. FA, follicular adenoma; FTC, follicular thyroid carcinoma; NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; HA, Hürthle cell adenoma; HCC, Hürthle cell carcinoma; PDTC, Poorly differentiated thyroid carcinoma arising in a well differentiated follicular neoplasm.
  Figure 2
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
  Fig. 2. The landscape of somatic mutations in follicular-patterned thyroid tumors according to histologic subtypes. All tumors with BRAF mutation had only p.K601E. Green color indicates point mutation. Purple color indicates promoter mutation. NIFTP, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PDTC, Poorly differentiated thyroid carcinoma arising in a well differentiated follicular neoplasm.
  Figure 3
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
  Fig. 3. Representative histologic images of the follicular-patterned thyroid tumors. A and B, Hürthle cell adenoma with an EZH1 Y642F mutation. A, The tumor has a complete thin fibrous capsule and shows a mixture of macrofollicular and microfollicular growth pattern. B, The majority of the tumor is composed of Hürthle cells. C and D, Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) with a NRAS Q61R mutation. C, The tumor is sharply demarcated from the normal thyroid tissue by a fibrous capsule. D, The tumor shows a follicular growth pattern and papillary carcinoma-like nuclear features (inset). E and F, Minimally invasive follicular thyroid carcinoma with a NRAS Q61R mutation. The tumor shows a mushroom-shaped invasion of tumor capsule (E) and follicular cells lacking nuclear features of papillary carcinoma (F). G and H, Poorly differentiated thyroid carcinoma arising from a preexisting follicular thyroid carcinoma. G, The tumor shows areas of well-differentiated follicular carcinoma (left) and poorly differentiated carcinoma with solid and trabecular growth pattern (right). H, Mitotic figures are seen (arrow) in the area exhibiting a trabecular pattern of growth. Concurrent NRAS Q61R and TERT C228T mutations were detected in this tumor. Hematoxylin and eosin stain; original magnification ×12 (A, C), ×400 (B, D, F, H), ×40 (E, G).
  Figure 4
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
  Fig. 4. Schematic representation of the distribution of EZH1 mutations in thyroid tumors across protein domains. Two hot spots (p.Q571R and p.Y642) are observed nearby and within the SET domain. Of 77 somatic mutations found in thyroid tumors, 13 were detected in our cohort. The SET domain contains histone methyltransferase and catalyzes the methylation of lysine 27 on histone H3 (H3K27).
  Figure 5
EZH1突变在滤泡性甲状腺肿瘤诊断中的临床应用(主要内容翻译)
  Fig. 5. The overall prevalence of EZH1 mutations in thyroid tumors based on the reports by TCGA study [5], Jung SH et al [8], Calebiro D et al [14], Yel L et al [15], Yoo SK et al [16], and present study.
  讨论
  大多数滤泡性甲状腺肿瘤与较低复发风险或较低的疾病特异性死亡率相关,常常以RAS基因点突变作为肿瘤驱动突变[1,5,16]。然而,单独用RAS突变不足以对滤泡性甲状腺肿瘤进行精确的风险分级,因为RAS突变可在从良性到高风险的一系列滤泡性甲状腺肿瘤中检测到。在本研究中,RAS突变的发生率在Hürthle细胞腺瘤中最低(17%)而在PDTC中最高(57%)。为了克服应用RAS突变的限制,我们研究了更多的基因突变类型,以便对滤泡性肿瘤进行风险分级。我们发现EZH1突变可见于RAS阴性滤泡性肿瘤中。13例EZH1突变的甲状腺肿瘤中,有11例(85%)为Hürthle细胞腺瘤而另2例分别为传统滤泡型腺瘤和微浸润Hürthle细胞癌。
  在本研究以及先前的文献报道中,EZH1突变主要见于良性甲状腺疾病,而极少见于恶性肿瘤(13.5% vs 0.7%)(图5)。所有伴EZH1突变的FTC(n=3)和Hürthle细胞癌(n=1)均为包膜微浸润型,无血管浸润[16]。有趣的是,EZH1突变尚未见于NIFTP中。我们还对浸润性包裹性滤泡型PTC(n=20)的EZH1突变进行分析,未见突变存在(表3)。
  伴EZH1突变的PTCs仅在TCGA研究中报道[5]。在其他研究(包括我们的研究)中,PTCs中未发现EZH1突变。TCGA研究报道的2例EZH1突变阳性的PTC病例,其1例为2.1cm包裹性嗜酸性滤泡亚型PTC伴EZH1 Y642F突变(患者ID TCGA-EM-A2OV),另1例为0.9cm界限清楚的滤泡亚型PTC伴EZH1 M349L突变(患者ID TCGA-DJ-A3UT)。在接受NIFTP的概念前,无论组织学生长模式和浸润状态如何,PTC核特征被认为是诊断PTC的金标准。然而,典型核特征的诊断界限对病理学工作者而言具有主观性。不可避免地,部分良性包裹性滤泡性肿瘤被错误诊断为包裹性滤泡型PTC,导致了PTC的过度诊断[17-19]。NIFTP和包裹性滤泡型PTC组织学诊断的一致标准于2016年由Nikiforov等公布[3]。在接纳NIFTP这一概念前,病理工作者在诊断PTC时对核特征的评估存在巨大差异[3,17]。当我们在cBioPortal评估了伴EZH1 Y642F突变的PTC病例的显微镜图像和病理报告后(补充图1),这些病例被重新分类为Hürthle细胞腺瘤,因为在显微镜图像和病理报告中并没有发现肿瘤包膜或血管浸润,且根据NIFTP病理专家工作组制定的核评分系统,其核评分为1分[1,3]。然而,不管肿瘤是包裹性嗜酸性滤泡型PTC还是Hürthle细胞腺瘤,将该惰性肿瘤与传统的PTC相区分是十分重要的。
  在先前的研究中,EZH1 Q571R突变仅见于成人自主功能性甲状腺腺瘤,而不见于其他甲状腺肿瘤包括儿童自主功能性甲状腺腺瘤、非功能性甲状腺结节、FTCs或PTCs[14]。然而,我们的研究显示,所有13名EZH1突变患者的血清T3、T4和TSH均正常。后续研究证实了EZH1 Q571R突变在高功能甲状腺腺瘤发展中的作用。另一项近期研究报道了EZH1 Q571R在两组腺瘤样结节中的发生率分别为8%(3/38)和9%(24/259)。然而,在该研究中的PTC和FTC(n=55)中未检测到EZH1突变[15]。
  组蛋白甲基化可能激活或抑制靶基因的转录,这取决于被甲基化的氨基酸残基以及组蛋白甲基化的程度[20]。EZH1基因编码组蛋白-赖氨酸N-甲基转移酶EZH1蛋白,为Polycomb抑制复合体2(PRC2)的组成部分[21,22]。PRC2复合体由EED、SUZ12和EZH1或EZH2组成[23]。EZH1和EZH2的SET结构域包含组蛋白甲基转移酶,可催化组蛋白H3的27位赖氨酸(H3K27)单甲基化、双甲基化和三甲基化,引起基因转录的抑制[21,23,24]。在多种肿瘤中,EZH1和EZH2的靶基因具有肿瘤抑制功能,影响了肿瘤细胞的增殖、浸润和转移[21,23,24]。肿瘤抑制基因的H3K27可以被EZH2三甲基化导致失活[23,24]。H3K27三甲基化水平的提高可见于转染EZH1 Q571R的HEK293细胞和两种大鼠甲状腺细胞转染模型中,并见于所有EZH1 Q571R突变的自主功能性甲状腺腺瘤中[14]。EZH1 Q571R突变的增殖潜能已在Fischer大鼠甲状腺细胞中用MTT细胞增殖法阐明[14]。
  我们使用蛋白质突变效应分析软件[PROVEAN](J. Craig Venter Institute, Rockville, MD & La Jolla, CA, USA)[25, 26]对点突变引起的EZH1氨基酸替换的功能效应进行了预测。两个突变热点(EZH1 Q571R和EZH1 Y642F)导致的蛋白改变可预测到有害效应(PROVEAN分数=-3.763和-3.629)。EZH1 M349L突变仅在1例PTC病例中被TCGA所报道[5]。突变导致的蛋白改变可预测到神经效应(PROVEAN分数=-0.623)。有趣的是,经TCGA数据库分析,1例伴EZH1 M349突变的PTC(TCGA-DJA3UT)并发NRAS Q61R突变,而1例伴EZH1 Y642F突变的PTC(TCGA-EM-A2OV)未见RAS突变。这些结果表明EZH1 M349突变对肿瘤发生作用微小。另一方面,EZH1 Q571R和EZH1 Y642F突变则对EZH1蛋白产生有害影响。
  TERT启动子突变在人类肿瘤中存在两处热点(chr5, 1,295,228 C>T (C228T) 和1,295,250 C>T (C250T))。它们可以促进原癌基因的转录活性[27,28]。关于甲状腺肿瘤的多篇文献表明TERT启动子突变更多见于侵袭性组织学类型的甲状腺癌中。这些突变与侵袭性肿瘤生物学行为、肿瘤复发和患者死亡率密切相关[7,28]。相比于单一突变的肿瘤,并发TERT启动子突变和BRAF或RAS突变的甲状腺癌的临床预后更差[28-30]。我们的研究中,所有7例TERT启动子突变的病例发展为远处转移。5例并发TERT启动子突变和NRAS或BRAF突变的患者发生肿瘤复发和放射性碘治疗耐受。1例死于疾病进展。
  总而言之,我们的研究提示,EZH1突变在临床上主要见于良性的无RAS突变的滤泡性肿瘤。RAS突变和BRAF K601E突变可见于良性、交界性和恶性滤泡性甲状腺肿瘤中。TERT启动子突变是侵袭性甲状腺肿瘤的有力标志。EIF1AX突变对甲状腺肿瘤的分子诊断影响有限,主要是因为其罕见的发生率。这些基因标志可用于甲状腺结节的诊断和风险分级。
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  本文出处:Jung CK, Kim Y, Jeon S,et al. Clinical utility of EZH1 mutations in the diagnosis of follicularpatterned thyroid tumors [J]. Human Pathology. Doi:10.1016/j/humpath.2018.04.018.[Epub ahead of pr
 
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