ABSTRACT
The classical mutation theory of cancer cannot adequately explain the findings of cancer epidemiology. Several decades of epidemiological studies have consistently shown that most cancers (70%–90%) are preventable and related to environmental factors [2-5]. Rapid increases in rates of colon cancer among migrants from low-to high-risk areas indicate that large international differences in cancer rate are due to environmental rather than genetic causes. Doll and Peto have suggested that differences in diet may account for 90% of the variation in rates among countries but the specific factors that are responsible have not been established [2]. Mutagens are found to be a relatively minor aspect of the environmental contribution to cancer. Even in cases where a carcinogen has mutagenic effects (smoking, radiation, etc.), it remains debatable as to the relative importance of the cytostatic=toxic effects versus the mutagenic effects of the carcinogen [6,7]. Many mutagens are not carcinogens. Defects in DNA repair systems do not always cause cancer [8,9]. Most incipient tumors and even advanced cancers regress naturally, inconsistent with the irreversibility of mutations [10]. Cancers of the same phenotype often have a different spectrum of gene mutations, whereas cancers with the same mutations have dissimilar clinical features. Normal cells rarely gain growth advantages but instead often undergo cell death or senescence when a mutation occurs or when an oncogene is activated [11,12]. The relatively stable genotypes and phenotypes of end stage cancer seem at odds with an enhanced mutation rate. Number of mutations and timing of onset vary greatly among different cancers. None of the hallmarks of cancer [13] cannot be generated by an epigenetic reprograming of wild-type genome or cannot find a match among the extremely large number of cell types in a human body. Some tumors such as teratomas have few mutations, and implantation of embryonic stem cells into many somatic tissues forms teratomas [14]. Cancer often contains aneuploidy but what causes aneuploidy remains unaccounted for by the mutation theory. Overall, this large body of facts contradicts the mutation theory.
