文章：

治疗相关癌变机制

Mechanisms of therapy-related carcinogenesis

原文发布日期：2005-11-18

DOI: 10.1038/nrc1749

类型: Review Article

开放获取: 否

要点：

1. Treatment for a first cancer is associated with a significantly increased risk of developing a second primary cancer compared with the general population. Such cancers are termed 'therapy-related' and can represent a significant source of mortality for cancer survivors.
2. Therapy-related cancers have been reported after structurally and mechanistically diverse treatments, in which the risk of developing these cancers is often dose dependent (such as for radiotherapy and alkylating agents).
3. Molecular, cellular and epidemiological evidence indicates the existence of discrete mechanisms of carcinogenesis. These could involve either direct targeting of crucial transforming genes and relatively short latency of disease onset, or indirect targeting by the acquisition of a predisposing cellular phenotype (genomic instability) in which disease latency is longer.
4. DNA double-strand breaks that are induced by chemotherapeutic topoisomerase inhibitors can lead to translocation of the mixed lineage leukaemia gene, as well as other crucial transforming genes.
5. Chemotherapeutic methylating agents and thiopurines can promote the emergence of cells with dysfunctional DNA-mismatch repair and concomitant genomic instability.
6. Radiotherapy and chemotherapy interact with other factors, such as hormonal status, cigarette smoking and genetic makeup, to modify the risk of developing a second cancer.
7. By understanding the risk factors for developing therapy-related cancers, and the mechanisms by which they develop, we might be able to prevent them or identify patients at high risk who might benefit from surveillance.

要点翻译：

1. 首次癌症的治疗与普通人群相比，发生第二种原发癌的风险显著增加。这类癌症被称为"治疗相关癌症"，可能成为癌症幸存者重要的死亡原因。
2. 结构和机制各异的治疗方案均有治疗相关癌症的报道，其发生风险通常呈剂量依赖性（如放疗和烷化剂治疗）。
3. 分子、细胞和流行病学证据表明存在不同的致癌机制。这些机制可能涉及直接靶向关键转化基因导致疾病潜伏期相对较短，也可能通过获得易感细胞表型（基因组不稳定性）进行间接靶向，此类情况疾病潜伏期较长。
4. 化疗拓扑异构酶抑制剂诱导的DNA双链断裂可能导致混合谱系白血病基因及其他关键转化基因的易位。
5. 化疗甲基化剂和硫嘌呤类药物可能促使出现DNA错配修复功能异常并伴随基因组不稳定性的细胞。
6. 放疗和化疗与激素状态、吸烟及遗传背景等其他因素相互作用，共同影响第二种癌症的发生风险。
7. 通过理解治疗相关癌症的危险因素及其发生机制，我们或能预防这类癌症，并识别出可能从监测中获益的高风险患者。

英文摘要：

Therapy-related cancers, defined as second primary cancers that arise as a consequence of chemotherapy and/or radiotherapy, are unusual in that they have a well-defined aetiology. Knowledge of the specific nature of the initiating exposure and exactly when it occurred has made it easier to identify crucial genetic events and to model these in vitro and in vivo. As such, the study of therapy-related cancers has led to the elucidation of discrete mechanisms of carcinogenesis, including DNA double-strand-break-induced gene translocation and genomic instability conferred by loss of DNA repair. Unsurprisingly, some of these mechanisms seem to operate in the development of sporadic cancers.

摘要翻译： 

治疗相关癌症，定义为因化疗和/或放疗而继发的第二原发癌，其不寻常之处在于具有明确的病因。由于知晓其始动暴露的具体性质及确切发生时间，人们更容易识别关键遗传事件，并在体外和体内进行建模。因此，治疗相关癌症的研究阐明了致癌的离散机制，包括DNA双链断裂诱导的基因易位以及因DNA修复缺失导致的基因组不稳定性。不出所料，其中一些机制似乎也在散发性癌症的发展中发挥作用。

原文链接：

Mechanisms of therapy-related carcinogenesis