根据癌症发病机制的最新发现，人们重新审视了癌症的发生。值得注意的是良性条件下突变癌症基因的检测。更重要的是，含有癌症基因突变的体细胞克隆在从早期发育到成年的正常组织中出现，但很少转化为癌症。此外，集群突变事件——kataegis、chromothripsis和chromoplexy——在癌症中广泛存在，在单一细胞灾难中产生点突变和染色体重排。这些观察结果与流行的体细胞突变理论相反，该理论认为癌症是由突变随着时间的推移逐渐积累而引起的。在沃丁顿的表观遗传景观框架内提出了不同的观点，其中肿瘤发生主要被视为细胞发育的破坏。细胞类型由其特定的基因表达谱定义，由基因调控网络决定，并且可以被视为网络动力学的吸引子状态：它们代表整个基因组中基因活动的特定的、自我稳定的模式。然而，大规模的突变事件重塑了景观拓扑，产生了异常的“非生理”吸引子。这是启动过程的关键。致癌基因和肿瘤抑制基因启动细胞向肿瘤表型的转化，从而驱动细胞增殖和克隆多样化。这种肿瘤发生的观点需要不同的治疗方法。© 2023 作者。基因、染色体和癌症由 Wiley periodicals LLC 出版。

Cancer initiation is revisited in light of recent discoveries in cancer pathogenesis. Of note is the detection of mutated cancer genes in benign conditions. More significantly, somatic clones, which harbor mutations in cancer genes, arise in normal tissues from early development through adulthood, but seldom do they transform into cancer. Further, clustered mutational events-kataegis, chromothripsis and chromoplexy-are widespread in cancer, generating point mutations and chromosomal rearrangements in a single cellular catastrophe. These observations are contrary to the prevailing somatic mutation theory, which states that a cancer is caused by the gradual accumulation of mutations over time. A different perspective is proposed within the framework of Waddington's epigenetic landscape wherein tumorigenesis is viewed primarily as a disruption of cell development. Cell types are defined by their specific gene-expression profiles, determined by the gene regulatory network, and can be regarded as attractor states of the network dynamics: they represent specific, self-stabilizing patterns of gene activities across the genome. However, large-scale mutational events reshape the landscape topology, creating abnormal "unphysiological" attractors. This is the crux of the process of initiation. Initiation primes the cell for conversion into a tumor phenotype by oncogenes and tumor suppressor genes, which drive cell proliferation and clonal diversification. This view of tumorigenesis calls for a different approach to therapy.© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.