Duesberg P H
Department of Molecular Biology, University of California, Berkeley 94720.
Med Oncol Tumor Pharmacother. 1987;4(3-4):163-75. doi: 10.1007/BF02934512.
The 20 known transforming onc genes of retroviruses are defined by sequences that are transduced from cellular genes, termed proto-oncogenes or cellular oncogenes. Based on these sequences, viral onc genes have been postulated to be transduced cellular cancer genes and proto-onc genes have been postulated to be latent cancer genes that can be activated from within the cell to cause virus-negative tumors. The hypothesis is popular because it promises direct access to cellular cancer genes. However, the existence of latent cancer genes presents a paradox since such genes are clearly undesirable. The hypothesis predicts (i) that viral onc genes and proto-onc genes are isogenic, (ii) that expression of proto-onc genes induces tumors, (iii) that activated proto-onc genes transform diploid cells upon transfection, like viral onc genes, and (iv) that diploid tumors exist that differ from normal cells only in transcriptionally or mutationally activated proto-onc genes. As yet, none of these predictions is confirmed. Moreover, the probability of spontaneous transformation in vivo is at least 10(9) times lower than predicted from the mechanisms thought to activate proto-onc genes. Therefore the hypothesis, that proto-onc genes are latent cellular oncogenes, appears to be an overinterpretation of sequence homology to structural and functional homology with viral onc genes. Here it is proposed that only rare truncations and illegitimate recombinations that alter the germline configuration of cellular genes, generate viral and possibly cellular cancer genes. The clonal chromosome abnormalities that are consistently found in tumor cells are microscopic evidence for rearrangements that may generate cancer genes. The clonality indicates that the tumors are initiated with, and possibly by, these abnormalities as predicted by Boveri in 1914 (Zur Frage der Entstehung maligner Tumoren, Jena, Fischer).
逆转录病毒的20种已知转化致癌基因由从细胞基因转导而来的序列所定义，这些细胞基因被称为原癌基因或细胞癌基因。基于这些序列，病毒致癌基因被假定为转导的细胞癌基因，而原癌基因被假定为潜在的癌基因，可在细胞内被激活从而导致无病毒肿瘤。该假说广受欢迎，因为它有望直接找到细胞癌基因。然而，潜在癌基因的存在却带来了一个悖论，因为这类基因显然是不受欢迎的。该假说预测：（i）病毒致癌基因和原癌基因是同基因的；（ii）原癌基因的表达会诱发肿瘤；（iii）像病毒致癌基因一样，激活的原癌基因在转染后会转化二倍体细胞；（iv）存在仅在转录或突变激活的原癌基因方面与正常细胞不同的二倍体肿瘤。到目前为止，这些预测均未得到证实。此外，体内自发转化的概率比从被认为激活原癌基因的机制所预测的至少低10⁹倍。因此，原癌基因是潜在细胞癌基因这一假说似乎是对与病毒致癌基因的序列同源性过度解读为结构和功能同源性。本文提出，只有罕见的截断和非法重组会改变细胞基因的种系构型，从而产生病毒及可能的细胞癌基因。肿瘤细胞中始终存在的克隆性染色体异常是可能产生癌基因的重排的微观证据。克隆性表明肿瘤如1914年博韦里所预测的那样（《论恶性肿瘤的起源》，耶拿，费舍尔）是由这些异常引发的，并且可能是由这些异常引发的。
