Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
Nat Rev Cancer. 2018 Aug;18(8):471-484. doi: 10.1038/s41568-018-0015-6.
In this Review, I present evidence supporting a multifactorial causation of childhood acute lymphoblastic leukaemia (ALL), a major subtype of paediatric cancer. ALL evolves in two discrete steps. First, in utero initiation by fusion gene formation or hyperdiploidy generates a covert, pre-leukaemic clone. Second, in a small fraction of these cases, the postnatal acquisition of secondary genetic changes (primarily V(D)J recombination-activating protein (RAG) and activation-induced cytidine deaminase (AID)-driven copy number alterations in the case of ETS translocation variant 6 (ETV6)-runt-related transcription factor 1 (RUNX1) ALL) drives conversion to overt leukaemia. Epidemiological and modelling studies endorse a dual role for common infections. Microbial exposures earlier in life are protective but, in their absence, later infections trigger the critical secondary mutations. Risk is further modified by inherited genetics, chance and, probably, diet. Childhood ALL can be viewed as a paradoxical consequence of progress in modern societies, where behavioural changes have restrained early microbial exposure. This engenders an evolutionary mismatch between historical adaptations of the immune system and contemporary lifestyles. Childhood ALL may be a preventable cancer.
在这篇综述中，我提出了支持儿童急性淋巴细胞白血病（ALL）多因素病因的证据，ALL 是儿科癌症的主要亚型之一。ALL 分两个离散的步骤发展。首先，在宫内由融合基因形成或超二倍体产生隐蔽的、白血病前克隆。其次，在这些病例中的一小部分中，后天获得的继发性遗传变化（主要是 ETS 易位变体 6（ETV6）- runt 相关转录因子 1（RUNX1）ALL 中 V(D)J 重组激活蛋白（RAG）和激活诱导胞苷脱氨酶（AID）驱动的拷贝数改变）驱动向显性白血病转化。流行病学和建模研究支持常见感染的双重作用。生命早期的微生物暴露具有保护作用，但在没有这些暴露的情况下，后期感染会引发关键的二次突变。风险还受到遗传、偶然和可能的饮食因素的影响。儿童 ALL 可以被视为现代社会进步的一个矛盾后果，在现代社会中，行为改变限制了早期的微生物暴露。这导致了免疫系统的历史适应性与当代生活方式之间的进化不匹配。儿童 ALL 可能是一种可预防的癌症。
