Medical Diagnosis
Vol. 09  No. 01 ( 2019 ), Article ID: 29418 , 7 pages
10.12677/MD.2019.91004

Application of Biomarkers for Common Cancers in Molecular Diagnosis

Jiandong Han, Meiling Wang, Gegentana, Yanqing Du, Fengying Liang, Eerdun*

Inner Mongolia Medical University, Hohhot Inner Mongolia

Received: Mar. 6th, 2019; accepted: Mar. 19th, 2019; published: Mar. 26th, 2019

ABSTRACT

There is increasing evidence that target-based drugs are only active in a population of selected molecules. Therefore, the identification of predictive biomarkers has become a necessary condition for improving the clinical development of these novel drugs. Mutation of the epidermal growth factor receptor (EGFR) or rearrangement of the ALK gene and BRAF mutation in melanoma in non-small cell lung cancer are clear examples of driving mutations. Predictive biomarkers can also identify subgroups of patients who are less likely to respond to a particular drug, such as KRAS mutations in colorectal cancer and anti-EGFR monoclonal antibodies. The discovery of novel driving molecule changes and the availability of drugs capable of selectively blocking this oncogenic mechanism have led to a rapid increase in the number of putative biomarkers that need to be evaluated in each individual patient. Introducing these techniques in clinical practice will increase the likelihood of identifying molecular targets in each patient and also allow for tracking the molecular evolution of the disease during treatment. By using these methods, personalized medicines can eventually be developed for cancer patients.

Keywords:Cancer, Marker, Diagnosis

常见癌症生物标记物在分子诊断中的应用

韩建冬,王美玲,格根塔娜,杜艳青,梁凤英,额尔敦*

内蒙古医科大学,内蒙古 呼和浩特

收稿日期:2019年3月6日;录用日期:2019年3月19日;发布日期:2019年3月26日

摘 要

越来越多的证据表明,基于靶标的药物仅在分子选择的患者群体中有活性。因此,预测性生物标志物的鉴定已成为改善这些新型药物的临床开发的必要条件。非小细胞肺癌中表皮生长因子受体(EGFR)的突变或ALK基因的重排以及黑素瘤中的BRAF突变是驱动突变的明显例子。预测性生物标志物还可以鉴定不太可能对特定药物有反应的患者亚组,如结肠直肠癌中的KRAS突变和抗EGFR单克隆抗体所示。新型驱动分子改变的发现和能够选择性阻断这种致癌机制的药物的可用性导致需要在每个单独患者中评估的推定生物标志物的数量的快速增加。在临床实践中引入这些技术将增加识别每个患者中的分子靶标的可能性,并且还允许在治疗期间跟踪疾病的分子进化。通过使用这些方法,最终可以为癌症患者开发个性化药物。

关键词 :肿瘤,标记物,诊断

Copyright © 2019 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).

http://creativecommons.org/licenses/by/4.0/

1. 引言

癌细胞的增殖,转移和分化的分子机制的发现为基于针对特定分子靶标的药物产生新的治疗方法提供了坚实的基础。在过去几年中,基于临床前研究提供的强有力的实践基础,已经开发了许多基于靶标的药物 [1] 。

通过体细胞突变和其他遗传畸变驱动人类恶性肿瘤的发现,促进了治疗干预目标和同时预测性生物标志物的鉴定。然而,已经证明在已选择的癌症类型中发生了已被定义为“癌基因成瘾”的特殊现象 [2] [3] [4] [5] 。事实上,一些含有多种遗传,表观遗传和染色体异常的癌症依赖于或“沉迷”于一个或几个基因,以维持恶性表型和细胞存活。鉴定这些基因会导致针对特定分子可识别的亚组患者开发高效抗肿瘤药物。表皮生长因子受体(EGFR)的突变或ALK基因在非小细胞肺癌(NSCLC)中的重排以及黑素瘤中的BRAF突变是驱动突变和对特定抑制剂治疗反应的预测生物标志物的明显例子。

2. 诊断学中肺癌的生物标记物

如结肠直肠癌(CRC)中的KRAS突变和抗EGFR单克隆抗体(MoAb)所示,这些药物不太可能对特定药物有反应。在这些情况下,生物标志物通常代表耐药机制。然而,当药物针对不携带其基因序列改变的靶标(例如CRC中的EGFR)时,鉴定预测性生物标志物并不容易 [6] [7] [8] 。事实上,必须强调的是,肿瘤中潜在的驱动突变的存在不足以确保患者对针对所鉴定的靶标的抑制剂起反应。这些发现表明潜在的驱动突变可能在维持肿瘤细胞生长和存活方面具有不同的作用 [9] 。此外,预测性生物标志物的鉴定应始终在临床试验中进行。如果没有用目标药物治疗的患者群体不能作为分析资料,则阴性预后因子可能容易被误认为是阴性预测标志物。

肺癌是世界上肿瘤死亡率的主要原因,可分为两大类,即小细胞肺癌(SCLC)和NSCLC。NSCLC约占肺癌的80%,并且包括不同的组织学类型,包括鳞状细胞癌和大细胞癌。在过去几年中,已经在肺腺癌患者中鉴定了许多不同的分子亚组。肺癌分子亚型的特征在于特定基因的突变,并且已经证明这些分子改变中的至少一些作为驱动突变。更重要的是,来自临床试验的证据已经导致NSCLC治疗规范的改变。EGFR基因的突变是在肺癌中第一个发现的生物标志物。EGFR在高达80%的人原发性NSCLC中表达,并且有证据表明它参与肺癌的发病机制。在早期临床试验中对EGFR-酪氨酸激酶抑制剂(TKIs)吉非替尼或厄洛替尼有反应的患者中分析EGFR基因后,已发现激活NSCLC中EGFR的突变。几乎所有对EGFR-TKI有反应的患者都检测到EGFR突变。这些突变通常在EGFR的TK结构域的外显子中发现,并且是点突变或框内小缺失或插入。虽然到目前为止已经描述了超过250个EGFR突变,但有两个突变,即外显子21中的单点突变,即L858R和外显子中的一系列小框内缺失占所有EGFR突变的约90%。EGFR突变在未选择的高加索人NSCLC患者中不常见 [10] 。

虽然EGFR突变与对EGFR-TKI的反应之间的相关性自用该药物的早期临床试验以来是明显的,但已假设其他几种生物标志物与敏感性相关(EGFR基因拷贝数变异,EGFR蛋白表达和AKT激活水平)。或EGFR-TKI的抗性(KRAS突变)。然而,随机III期临床试验的结果已经清楚地证明EGFR突变是预测对EGFR-TKI敏感性的唯一可靠标记。观察到EGFR-TKI作为一线治疗与EGFR突变患者化疗相比,导致无进展生存期(PFS)延长,EGFR-TKI治疗已成为EGFR突变体推荐的一线治疗方法。EGFR-TKI吉非替尼已于2009年在欧洲被批准用于治疗EGFR突变。因此,为了选择最适合NSCLC患者的一线治疗 [11] 。

其他基因如KIF5B,TGF和ROS1也被描述为与ALK形成融合产物。EML4-ALK融合癌基因导致ALK酪氨酸激酶的异常激活和下游信号传导途径的组成性激活。已经在NSCLC中检测到这种融合。患有ALK重排的NSCLC患者往往更年轻,吸烟史很短或没有。ALK重排仅在腺癌中发现,并且与印戒细胞组织学或与丰富的细胞内粘蛋白相关。EML4-ALK改变与EGFR和KRAS突变相互排斥。虽然一些研究表明与男性性别有关,但这种突变与患者的种族和性别没有明显关联。在ALK阳性晚期NSCLC患者中,ALK抑制剂克唑替尼的I期和II期试验显示出高反应率和低副作用。根据I期和II期临床试验数据,美国食品和药物管理局于2011年8月批准了克唑替尼治疗携带ALK重排的NSCLC患者 [12] 。

最近报道的ROS1基因与不同伴侣的重排在大约1%的NSCLC中发生。ROS1是胰岛素受体家族的受体酪氨酸激酶,编码ROS1的基因位于染色体6q22上 [13] 。ROS1融合主要在年轻且从不吸烟的腺癌患者中发现。重要的是,临床前数据表明克唑替尼可以抑制ROS1阳性肿瘤的增殖,并且在携带ROS1重排的NSCLC患者中观察到对克唑替尼的显着反应。在NSCLC中发现了许多其他驱动的突变。KRAS突变在大约30%的腺癌中发现,在吸烟者中更常见。尽管目前尚不能获得靶向RAS蛋白的药物,但已建议对KRAS突变进行评估以鉴定对EGFR-TKI具有抗性的患者。由于KRAS,EGFR和ALK突变是相互排斥的,因此KRAS突变的存在可能预测对EGFR-TKI和克唑替尼的抗性,因为它排除了这些药物的靶标存在的可能性 [14] 。还鉴定了携带编码ErbB-2,BRAF,PI3K,AKT1,MEK1和NRAS的基因突变的NSCLC腺癌亚组。然而,尚未获得一致的临床数据,证明这些突变的存在与对特定抑制剂的反应相关。

3. 诊断学中乳腺癌的生物标记物

乳腺癌(BC)是女性中最常见的恶性肿瘤,每年全世界诊断出新病例超过一百万。乳腺癌是第一种可用于预测性生物标志物的实体瘤 [15] 。事实上,定义早期和晚期乳腺癌治疗建议的主要参数是雌激素受体(ER),孕酮受体(PgR)和ErbB-2(HER2)状态。激素受体状态决定了对乳腺癌患者使用内分泌治疗,现在可以使用不同类型的内分泌药物来治疗激素受体阳性患者 [16] 。ErbB-2的表达与单克隆抗体曲妥珠单抗和TKI拉帕替尼的敏感性相关。这些标记通过使用免疫组织化学和荧光原位杂交(FISH)进行评估 [17] 。

基因表达谱分析技术的出现允许根据其基因表达模式将乳腺癌分为五个主要亚组。最近发现了一个名为“claudin-negative”的第六组。更重要的是,这些技术可以识别与乳腺癌患者中明显不同的临床结果相关的基因特征。然而,迄今为止尚未显示这些特征以预测BC中对特定药剂的反应的结果 [18] 。BRCA1和BRCA2是参与维持基因组完整性的肿瘤抑制基因。这些基因中的种系突变识别出患乳腺癌和卵巢癌的风险增加的个体。

BRCA1相关肿瘤通常表现出三重阴性表型和基底样形态,而BRCA2相关乳腺癌则是一个更加异质的组 [19] 。在BRCA缺陷肿瘤中的新治疗方法是基于抑制聚(ADP-核糖)聚合酶(PARP),一种参与修复单链断裂的酶 [20] 。BRCA相关肿瘤具有HR缺陷并且不能修复双链断裂。对DNA修复的替代机制的抑制导致多个DNA断裂的积累,因此缺乏同源修复机制的肿瘤细胞总是经历凋亡而正常组织不受影响。在BRCA相关肿瘤患者中引入PARP抑制剂代表了基于合成致死方法的第一种治疗方案。目前在乳腺癌的临床试验开发中至少有五种PARP抑制剂 [21] 。然而,这些药物尚未被批准用于治疗BRCA缺陷性肿瘤。其他几种信号转导抑制剂正在乳腺癌患者的临床开发中,并且为乳腺癌患者选择最合适的治疗所需的生物标记物的数量可能在未来十年继续增加。

4. 诊断学中大肠癌的生物标记物

大肠癌是全球第三大常见癌症,约占所有癌症死亡人数的10% [22] 。在过去十年中,靶向药物(例如抗EGFR和抗血管生成药物)的临床开发显着改善了大肠癌患者的存活。迄今为止,关于反应预测标志物的最相关数据涉及的是抗EGFR剂 [23] [24] [25] [26] 。临床数据强烈支持EGFR途径参与CRC的发病机制和进展。西妥昔单抗和帕尼单抗是两种MoAb,其结合并使EGFR的细胞外结构域失活,从而导致其下游信号传导的抑制。当用作单一药剂(帕尼单抗和西妥昔单抗)或与标准化疗(西妥昔单抗)组合时,这些药剂已被批准用于治疗晚期大肠癌。尽管EGFR蛋白在约85%的结肠直肠肿瘤中表达,但只有一组患有晚期CRC的患者受益于抗EGFR MoAb的治疗。该观察结果强调了鉴定对这些药物的反应或抗性标记的必要性 [27] [28] [29] [30] 。在这方面,已经在几个不同的研究中研究了KRAS突变在抗EGFR单克隆抗体抗性中的作用。

许多回顾性研究已经清楚地证明,KRAS突变的存在与西妥昔单抗和帕尼单抗的反应丧失有关。美国和欧洲卫生当局仅限于单独或与化疗联合使用抗EGFR MoAb,仅限于患有KRAS野生型肿瘤的患者。有趣的是,最近的研究表明,患有G13D KRAS突变的患者可能确实对抗EGFR MoAb有反应。然而,到目前为止已经报道了对比结果,并且具有G13D突变的患者目前被排除在用这些药剂治疗之外。密码子61和146中的突变也导致KRAS的活化。一项针对欧洲联盟的大型回顾性研究表明,密码子61的突变具有与密码子12突变类似的不良反应,而密码子146突变不影响西妥昔单抗的功效。然而,这些发现尚未在随机临床试验中得到证实。

用西妥昔单抗或帕尼单抗治疗的患者的回顾性亚组分析表明携带NRAS,BRAF,PIK3CA突变或显示PTEN表达缺失的患者可能确实对抗EGFR剂具有抗性。然而,这些发现是通过分析在临床试验或临床实践中用EGFR MoAb作为单一药剂或与伊立替康联合治疗的患者的结果而获得的,目的是恢复对该药物的抗性。此外,这些结果尚未在随机临床试验中得到证实。例如,来自西妥昔单抗的CRYSTAL研究加上FOLFIRI与FOLFIRI作为转移性大肠癌患者的一线治疗的数据表明,BRAF突变患者可能受益于西妥昔单抗治疗。因此,没有一致和充分的数据来排除在这些亚组患者中使用抗EGFR药物 [30] [31] [32] [33] [34] 。

一些体细胞突变可能提供重要的预后信息。例如,BRAF突变与CRC患者的较差结果密切相关。KRAS突变的预后作用更受争议,因为已经发现它们与一些研究中预后较差相关,但已报道了对比结果。最后,最近的研究表明,EGFR配体双调蛋白(AREG)和表皮调节蛋白(EREG)的高水平表达与CRC患者对抗EGFR MoAb的反应有关。这些数据表明在CRC中调节下游EGFR信号通路主要取决于AREG和EREG与KRAS野生型患者中ErbB受体的结合。因此,这些配体的更高表达导致EGFR途径的活化增加和对抗EGFR MoAb的敏感性。

5. 展望

1990年以前,不同肿瘤类型的治疗主要基于患者个体的临床病理类型、疾病分期和可选用的细胞毒药物,癌症治疗还处于探索水平,亦无从讨论个体化癌症医疗。到了20世纪末,分子靶向药物占领了癌症研究的主战场,成功研发的新药不胜枚举,例如:曲妥珠单抗、威罗菲尼、克唑替尼。靶向药物的靶点基因测序目前已成为临床工作中重要的一部分,也是癌症生物标记物重要的发展部分。分子靶向药物的发展和广泛使用,使得携带不同分子信息亚组的患者得以接受有效的治疗。但仅根据分子亚组进行治疗,而非患者个体进行治疗的医学只能称之为“分层医学”,肿瘤异种移植模型等概念的提出,将癌症标记物带入了新的个体化癌症医疗时代。

文章引用

韩建冬,王美玲,格根塔娜,杜艳青,梁凤英,额尔敦. 常见癌症生物标记物在分子诊断中的应用
Application of Biomarkers for Common Cancers in Molecular Diagnosis[J]. 医学诊断, 2019, 09(01): 17-23. https://doi.org/10.12677/MD.2019.91004

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