Aneuploidy and Cancer: From correlation to causation
Aneuploidy and Cancer: From correlation to causation
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DOI：
10.1159/000092963
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Hehlmann, Ruediger
中科院分区：
文献类型：
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作者：
Duesberg, Peter;Li, Ruhong;Hehlmann, Ruediger
传统的遗传理论未能解释为什么癌症没有在新生儿中发现，因此不能遗传；(2)在被致癌物“启动”后几年到几十年才发展；(3)是非诱变致癌物引起的；(4)染色体和表型“不稳定”；(5)携带癌症特异性非整倍体；(6)形成多基因表型；(7)非选择性表型，如多药耐药、转移或对非原生位点的亲和力，以及非肿瘤发生所必需的“不朽”；(8)不含致癌突变。相反，我们提出癌症是一种染色体疾病：因此，致癌物通过非特异性非整倍体启动染色体进化。非整倍体破坏了数千个基因的平衡，破坏了分离、合成和修复染色体的蛋白质组。因此，非整倍体是核型-表型变异的稳定来源，用经典达尔文的术语来说，癌症特异性非整倍体的选择促进了癌细胞的进化和随后的恶性“进展”。这些变异的比率与非整倍性的程度成正比，并且可以超过常规突变的4-7个数量级。这使得癌细胞成为具有独特但不稳定核型的新细胞“物种”，而不是突变细胞。癌症特异性非整倍体通过数千个基因的异常剂量产生复杂的恶性表型，就像21三体产生唐氏综合症一样。因此，癌症是一种染色体疾病而不是遗传疾病。染色体理论解释了(1)癌症的非遗传性，因为非整倍体是不可遗传的；(2)竞争性新物种进化的可能性较低，“肿瘤潜伏期”较长；(3)非选择性表型通过基因搭便车在选择性染色体上，和(4)“不朽”，因为染色体变异中和负突变和适应抑制条件比常规突变快得多。基于这篇文章，我们在2005年的《细胞肿瘤学》杂志上发表了一篇类似的文章，题为“癌症的染色体基础”；27日:293 - 318。
Conventional genetic theories have failed to explain why cancer (1) is not found in new-borns and thus not heritable;(2) develops only years to decades after ‘initiation'by carcinogens;(3) is caused by non-mutagenic carcinogens;(4) is chromosomally and phenotypically ‘unstable';(5) carries cancer-specific aneuploidies;(6) evolves polygenic phenotypes;(7) nonselective phenotypes such as multidrug resistance, metastasis or affinity for non-native sites and ‘immortality'that is not necessary for tumorigenesis;(8) contains no carcinogenic mutations. We propose instead that cancer is a chromosomal disease: Accordingly, carcinogens initiate chromosomal evolutions via unspecific aneuploidies. By unbalancing thousands of genes aneuploidy corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is thus a steady source of karyotypic-phenotypic variations from which, in classical Darwinian terms, selection of cancer-specific aneuploidies encourages the evolution and subsequent malignant'progressions' of cancer cells. The rates of these variations are proportional to the degrees of aneuploidy, and can exceed conventional mutation by 4–7 orders of magnitude. This makes cancer cells new cell'species' with distinct, but unstable karyotypes, rather than mutant cells. The cancer-specific aneuploidies generate complex, malignant phenotypes, through the abnormal dosages of the thousands of genes, just as trisomy 21 generates Down syndrome. Thus cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) nonheritability of cancer, because aneuploidy is not heritable;(2) long ‘neoplastic latencies' by the low probability of evolving competitive new species;(3) nonselective phenotypes via genes hitchhiking on selective chromosomes, and (4)‘immortality', because chromosomal variations neutralize negative mutations and adapt to inhibitory conditions much faster than conventional mutation. Based on this article a similar one, entitled “The chromosomal basis of cancer', has since been published by us in Cellular Oncology 2005; 27: 293–318.