Savage Philip
Department of Oncology, Brighton and Sussex University Hospitals, Brighton, United Kingdom.
Front Genet. 2020 Jun 9;11:426. doi: 10.3389/fgene.2020.00426. eCollection 2020.
Cytotoxic DNA damaging chemotherapy brings clinical benefits in the treatment of many metastatic malignancies. However routine curative treatment remains restricted to a small number of malignancies including acute leukemia, high grade lymphoma, germ cell tumors, gestational malignancies and some of the rare childhood cancers. The detailed explanation for this dramatic divergence in outcomes remains to be elucidated. However, we have previously argued that there is a strong correlation between presence of the unique genetic events of immunoglobulin gene variable/diversity/joining (VDJ) recombination, somatic hypermutation (SHM), meiosis, nuclear fusion and gastrulation occurring in cells of origin of these malignancies and their high sensitivity to DNA damaging chemotherapy. In this study we have reviewed some of the basic physiological information relating to the specialized activity and sensitivity to DNA damage mediated apoptosis of normal cells undergoing these processes. In each of unique genetic events there are dramatic changes in apoptotic sensitivity. In VDJ recombination and somatic hypermutation over 95% of the cells involved undergo apoptosis, whilst in meiosis and nuclear fusion there are dramatic short term increases in the apoptotic sensitivity to DNA damage. It is apparent that each of the malignancies arising during these processes retains some of the unique phenotype associated with it. The impact of the physiological differences is most clearly seen in the two non-mutational malignancies. Gestational choriocarcinoma which arises shortly after nuclear fusion is routinely curable with chemotherapy whilst CIMP-positive ependymomas which is not linked to any of the unique genetic events is highly resistant. A similar pattern is found in a pair of malignancies driven by a single driver mutation. Infantile acute lymphoblastic leukemia (ALL) arises in a cell undergoing the early stages of VDJ recombination and has a 40% cure rate in contrast pediatric rhabdoid malignancy which is not linked to a unique genetic event responds very poorly to chemotherapy treatment. The physiological changes occurring in cancer cells at the time of the malignant transformation appear to have a major impact on the subsequent sensitivity to chemotherapy and curability. New therapies that impact on these pathways may be of therapeutic value.
细胞毒性DNA损伤化疗在许多转移性恶性肿瘤的治疗中带来了临床益处。然而，常规的根治性治疗仍然局限于少数恶性肿瘤，包括急性白血病、高级别淋巴瘤、生殖细胞肿瘤、妊娠相关恶性肿瘤以及一些罕见的儿童癌症。这种显著的疗效差异的详细解释仍有待阐明。然而，我们之前认为，这些恶性肿瘤起源细胞中发生的免疫球蛋白基因可变区/多样性区/连接区（VDJ）重组、体细胞超突变（SHM）、减数分裂、核融合和原肠胚形成等独特遗传事件的存在与它们对DNA损伤化疗的高敏感性之间存在很强的相关性。在本研究中，我们回顾了一些与经历这些过程的正常细胞的特殊活性以及对DNA损伤介导的凋亡敏感性相关的基本生理信息。在每一个独特的遗传事件中，凋亡敏感性都有显著变化。在VDJ重组和体细胞超突变中，超过95%的相关细胞会发生凋亡，而在减数分裂和核融合中，对DNA损伤的凋亡敏感性会有显著的短期增加。显然，在这些过程中出现的每一种恶性肿瘤都保留了一些与之相关的独特表型。生理差异的影响在两种非突变性恶性肿瘤中最为明显。核融合后不久出现的妊娠绒毛膜癌通常可以通过化疗治愈，而与任何独特遗传事件均无关联的CIMP阳性室管膜瘤则具有高度耐药性。在由单一驱动突变驱动的一对恶性肿瘤中也发现了类似的模式。婴儿急性淋巴细胞白血病（ALL）发生在经历VDJ重组早期阶段的细胞中，治愈率为40%，相比之下，与独特遗传事件无关的儿童横纹肌肉瘤对化疗治疗反应很差。恶性转化时癌细胞中发生的生理变化似乎对随后的化疗敏感性和治愈率有重大影响。影响这些途径的新疗法可能具有治疗价值。
