为什么一些癌症幸存者会在多年后患上第二种癌症
既往治疗、遗传基因和共同的生物学机制如何为一种全新的、无关的癌症埋下伏笔,即使距第一种癌症消失已过去很久

要点
- •第二原发癌是一种在遗传上不同的新癌症,不同于原癌症复发或转移到新的部位。
- •放射治疗可能增加治疗区域内或附近出现新癌症的风险,这类癌症通常在治疗十年甚至更久后才出现。
- •烷化剂类化疗药物和拓扑异构酶II抑制剂与延迟出现的血液肿瘤相关,例如治疗相关性白血病和骨髓增生异常综合征。
- •克隆性造血是指发生突变的血液干细胞比邻近细胞增殖更多;这一过程可能因化疗而加快,并促成日后出现血液肿瘤。
- •遗传性突变,例如导致Li-Fraumeni综合征的突变或与BRCA1/2相关的突变,会提高一生中发生多种独立原发癌的可能性。
- •癌变场描述了这样一种情况:一大片受到相同损伤的组织区域,随着时间推移可能独立产生多个肿瘤。
- •儿童癌症幸存者面临显著更高的第二种癌症长期风险,主要是因为治疗时年龄较小,且此后还拥有数十年的生命时间。
- •基因组研究有时可以在肿瘤中检测到突变特征,并发现其与既往化疗或放射暴露留下的已知模式相符。
一名癌症幸存者在多年后被诊断出新癌症,并不一定意味着复发。原来的肿瘤并没有回来,也没有转移到新的部位。相反,这是另一种癌症形成了:有时发生在完全不同的器官,有时则在首次诊断数十年后才出现。医生将其称为第二原发癌:一种独立的新疾病,而不是第一种癌症的延续。要理解这种情况为何发生,就需要放下这样一种令人安心但并不准确的想法:癌症一旦得到治疗,身体的风险就会简单地恢复为零。
“第二种”并不意味着“复发”
治疗后可能发生三种截然不同的情况,而它们很容易混淆。复发是原始肿瘤的细胞在同一部位重新生长。转移则是同一批原始癌细胞前往新的器官,仍然带有与第一种肿瘤相同的遗传特征。第二原发癌则两者都不是。它是一群独立形成的细胞,并自行积累了另一套致癌变化。医生通常可以通过观察肿瘤的遗传构成来区分这些情况,因为第二原发癌在分子层面通常与第一种癌症完全不同。这一区分具有临床意义,因为第二原发癌会被作为一种独立疾病来治疗,而不是被视为第一次治疗失败的信号。
治疗本身如何埋下隐患
用于治愈或控制第一种癌症的治疗,在少数患者中可能促成日后出现新的癌症。放射治疗就是一个有充分记录的例子。对癌症幸存者进行的长期研究,包括一项针对数万名睾丸癌患者的大型分析显示,在曾接受照射的区域内或附近出现新癌症的风险有所增加。这种风险不会立即出现。它通常会在一段潜伏期后显现,即从受到某种暴露到最终由此导致癌症之间的时间间隔,往往是在治疗十年甚至更久以后。
某些化疗药物也存在类似但机制不同的风险。其中两类药物——烷化剂和拓扑异构酶II抑制剂——与一种延迟出现的血液肿瘤相关,这种肿瘤称为治疗相关性髓系肿瘤,包括急性髓系白血病以及一种相关的骨髓疾病——骨髓增生异常综合征。烷化剂通过化学方式损伤DNA链;拓扑异构酶II抑制剂则会干扰一种负责管理细胞内DNA盘绕和解旋的酶。两者都可能留下DNA断裂,而这些断裂有时只能得到不完美的修复;这种不完美的修复有时会成为多年后形成新癌症的第一步。
血液中隐藏的突变
这些延迟出现的血液肿瘤,部分原因在于一种几乎每个人随着年龄增长都会悄然发生的过程:克隆性造血。在数十年间,造血干细胞偶尔会获得随机突变。通常这并无害处。但有时,一个发生突变的干细胞开始比邻近细胞增殖得更快,逐渐在一个人的血细胞中占据越来越大的比例,有点像某一种酵母菌株慢慢在一批发酵面团中占据主导地位。
化疗似乎会加快这一过程。针对年龄相关克隆性造血的研究已经在普通人群中确立了这一现象;而后续的基因组研究则显示了更具体的情况:在一些后来发生治疗相关性白血病的患者中,携带TP53基因变化的突变克隆,在化疗开始前就已经悄悄存在于血液中。治疗未必是从头产生了这一突变。它可能只是赋予了原本已经存在的突变克隆竞争优势,使其能够在多年后扩增为完整的白血病。
遗传风险:从一开始就拥有“先发优势”
对一些幸存者来说,原因与既往治疗完全无关。生殖系突变是从父母遗传而来的基因变化,从出生起就存在于身体的每一个细胞中,并可能在一生中提高多个器官发生癌症的风险。这方面的奠基性发现来自对一些癌症负担异常高且类型多样的家族的研究:遗传学家David Malkin及其同事发现,TP53基因的遗传性突变是Li-Fraumeni综合征的基础。这种疾病与乳腺癌、肉瘤以及其他几种肿瘤类型相关,而这些肿瘤可能在同一个人的一生中不同阶段出现。遗传性BRCA1和BRCA2突变的作用原理类似:它们提高一生中发生多种原发癌的可能性,而不是将风险局限于单一部位。由于这些突变存在于每个细胞中,一种癌症得到治疗后,升高的风险并不会随之消失。
同一组织,多种肿瘤
有时,第二种癌症会出现在与第一种癌症大致相同的区域,但既没有共同的遗传性突变,也没有明确的治疗关联。一种解释是癌变场,这一概念由病理学家Danely Slaughter于20世纪50年代在研究口腔癌时首次提出。其观点是,一大片组织,而不仅仅是某个单独部位,可能受到同一种有害影响,例如烟草烟雾、慢性刺激或其他共同暴露。随着时间推移,整个“场”都可能积累早期遗传变化,使多个相互独立的组织区域都处于容易癌变的状态。结果可能表现为多年间接连出现的一系列无关肿瘤,而这些肿瘤实际上并非来自同一个祖细胞,而是共同起源于受损组织。
儿童癌症:更长的风险酝酿期
与成年后接受治疗的人相比,儿童癌症幸存者面临的第二种癌症长期负担明显更高。儿童癌症幸存者研究(Childhood Cancer Survivor Study)通过数十年的追踪,已经充分记录了这种风险,并显示其可持续至成年期。部分原因很简单:一名6岁接受治疗的儿童,比一名70多岁接受治疗的人多出五六十年的生命时间,让一种发展缓慢、与治疗相关的癌症有机会显现。发育中的组织也可能对放射治疗和化疗的长期影响更加敏感。暴露时年龄较小,再加上此后漫长的岁月,这两者共同解释了为什么儿童癌症幸存者项目强调终身随访,而不是在患者成年后就结束医疗照护。
读取DNA留下的“伤痕”
基因组研究增加了一类更新、更直接的证据。对数千种肿瘤中的DNA损伤模式进行编目的大规模研究,已经发现了突变特征,即特定暴露在基因组中留下的、具有特征性的指纹。某些化疗药物和放射治疗往往会以可识别的方式损伤DNA;在日后出现的肿瘤中追踪这些特征,可以为早期治疗曾促成该肿瘤这一观点提供分子层面的支持。这种方法目前仍是一种研究工具,而不是常规临床实践,但它强化了这样一种观点:一些第二原发癌确实在自身内部留下了导致其形成原因的、可以读取的直接记录。
未解问题:免疫系统的警戒能力会发生变化吗?
目前仍在积极研究的一个问题是,癌症治疗后,免疫系统识别并清除异常细胞的能力是否会发生变化。免疫衰老,即随着年龄增长而出现的免疫功能逐渐下降,在一般人群中已经得到充分认识。但癌症治疗是否会以一种具有实质意义的方式加速这一过程,并具体使新的恶性细胞获得立足和发展的机会,目前尚无定论;现有证据也不足以支持任何明确结论。
综合来看,这些线索并没有指向第二种癌症的单一原因。它们指向几条有时相互重叠的路径:治疗的持久影响、遗传易感性、共同的组织暴露,以及在更长生命过程中正常积累的突变。这并不意味着第二种癌症是癌症幸存者必须付出的代价。对大多数幸存者来说,相对风险的增加所对应的是幅度有限的绝对风险;这正是为什么相关风险会通过有计划的长期监测来追踪,而不是被视为必然结果。
常见问题
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Holt, Chen Hong, Eun Pyo Hong, Jongwhi H. Hong, Gerrit K. Hooijer, Henrik Hornshøj, Fumie Hosoda, Yong Hou, Volker Hovestadt, William Howat, Alan P. Hoyle, Ralph H. Hruban, Jianhong Hu, Taobo Hu, Xing Hua, Kuan-lin Huang, Mei Huang, Mi Ni Huang, Vincent Huang, Yi Huang, Wolfgang Huber, Thomas J. Hudson, Michael Hummel, Jillian A. Hung, David Huntsman, Ted R. Hupp, Jason Huse, Matthew R. Huska, Barbara Hutter, Carolyn M. Hutter, Daniel Hübschmann, Christine A. Iacobuzio-Donahue, Charles David Imbusch, Marcin Imielinski, Seiya Imoto, William B. Isaacs, Keren Isaev, Shumpei Ishikawa, Murat Iskar, S. M. Ashiqul Islam, Michael Ittmann, Sinisa Ivkovic, Jose M. G. Izarzugaza, Jocelyne Jacquemier, Valerie Jakrot, Nigel B. Jamieson, Gun Ho Jang, Se Jin Jang, Joy C. Jayaseelan, Reyka Jayasinghe, Stuart R. Jefferys, Karine Jegalian, Jennifer L. Jennings, Seung-Hyup Jeon, Lara Jerman, Yuan Ji, Wei Jiao, Peter A. Johansson, Amber L. Johns, Jeremy Johns, Rory Johnson, Todd A. 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团队审阅: 本文由以下人员审阅 Canceria Research Team

