Moustacchi E
UMR 218, CNRS, Institut Curie, Paris.
Bull Acad Natl Med. 1998;182(1):33-46; discussion 47.
The initiation step of the carcinogenic process consists in an alteration of genes playing a central role in the cellular life. The next steps of promotion and progression result from anomalies in the response to growth factors, to hormones and/or from the action of tumor promotors leading to cellular hyperplasia. This process generally leads to genetic instability of the initiated cell which in turn allows selection of malignant and invasive clones. The production of DNA damage by physical or chemical agents is dose-dependent. The error-free enzymatic repair processes including excision resynthesis of base damage or of altered nucleotides allow the restitution of intact DNA. The error-prone repair systems permit survival in association with transmissible alterations (genes and chromosomal mutations). Absence of repair leads to cytotoxicity, programmed cell death or disruption of cell cycle control leading to a pretumoral state. The major role played by mutations in the initiation of carcinogenesis is evidenced by the existence of genetic syndromes associated to hypersensitivity to genotoxic agents, defects in DNA repair capacity, anomalies in the expression of certain genes (including the tumor suppressor p53 gene, etc.) and an elevated predisposition to cancer. Xeroderma pigmentosum which is defective in excision-repair, ataxia telangiectasia and Fanconi anemia which are associated to anomalies in DNA recombination and the familial type of colon cancer HPNCP due to inefficient mismatch repair constitute paradigm for this fundamental notion. Alterations in the capacity to rejoin radiation induced DNA strand breaks appears to be associated to over-reactions to radiotherapy of cancer patients. Also the predisposition to develop secondary thyroid tumors following treatment of a primary cancer in childhood seems to involve the same defect. The existence in the general population of heterozygotes for such DNA repair genes should be taken into account for risk evaluation to therapeutic and environmental exposures.
致癌过程的起始步骤在于改变在细胞生命中起核心作用的基因。促进和进展的后续步骤源于对生长因子、激素反应的异常，和/或源于肿瘤促进剂导致细胞增生的作用。这个过程通常导致起始细胞的基因不稳定，进而使得恶性和侵袭性克隆得以选择。物理或化学剂造成的DNA损伤的产生是剂量依赖性的。包括碱基损伤或改变的核苷酸切除再合成在内的无差错酶修复过程可使完整的DNA得以恢复。易错修复系统允许细胞在伴有可传递改变（基因和染色体突变）的情况下存活。缺乏修复会导致细胞毒性、程序性细胞死亡或细胞周期控制的破坏，从而导致癌前状态。致癌作用起始中突变所起的主要作用可由以下情况证明：存在与对基因毒性剂过敏、DNA修复能力缺陷、某些基因（包括肿瘤抑制基因p53等）表达异常以及患癌易感性增加相关的遗传综合征。着色性干皮病存在切除修复缺陷，共济失调毛细血管扩张症和范科尼贫血与DNA重组异常有关，而家族性结肠癌HPNCP由于错配修复效率低下，这些都构成了这一基本概念的范例。辐射诱导的DNA链断裂重新连接能力的改变似乎与癌症患者对放疗的过度反应有关。同样，儿童期原发性癌症治疗后发生继发性甲状腺肿瘤的易感性似乎也涉及相同的缺陷。在对治疗和环境暴露进行风险评估时，应考虑到普通人群中此类DNA修复基因杂合子的存在。
