Duesberg Peter, Li Ruhong, Fabarius Alice, Hehlmann Ruediger
Department of Molecular and Cellular Biology, Donner Laboratory, UC Berkeley, Berkeley, Calif., USA.
Contrib Microbiol. 2006;13:16-44. doi: 10.1159/000092963.
Conventional genetic theories have failed to explain why cancer (1) is not found in newborns 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.
（1）在新生儿中未被发现，因此不具有遗传性；（2）仅在致癌物“引发”后的数年至数十年才会发生；（3）由非诱变致癌物引起；（4）在染色体和表型上“不稳定”；（5）具有癌症特异性非整倍体；（6）进化出多基因表型；（7）具有非选择性表型，如多药耐药性、转移或对非天然位点的亲和力以及“永生”，而这些对于肿瘤发生并非必要；（8）不包含致癌突变。我们反而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引发染色体进化。非整倍体通过使数千个基因失衡，破坏了负责染色体分离、合成和修复的蛋白质团队。因此，非整倍体是核型 - 表型变异的稳定来源，从经典达尔文主义的角度来看，对癌症特异性非整倍体的选择促进了癌细胞的进化及随后的恶性“进展”。这些变异的速率与非整倍体的程度成正比，并且可比传统突变高出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”，而非突变细胞。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，就如同21三体综合征产生唐氏综合征一样。因此，癌症是一种染色体疾病而非基因疾病。染色体理论解释了：（1）癌症的非遗传性，因为非整倍体不具有遗传性；（2）由于进化出具有竞争力的新物种的概率较低，所以存在较长的“肿瘤潜伏期”；（3）通过选择性染色体上的搭便车基因产生非选择性表型；（4）“永生”，因为染色体变异比传统突变更快地中和负面突变并适应抑制性条件。基于本文，我们随后在《细胞肿瘤学》2005年第27卷第293 - 318页发表了一篇类似的文章，题为《癌症的染色体基础》。
