after reading the paper by cristian tomasetti and bert vogelstein ( 1 ) and the following comments , including those from the world health organization international agency for cancer research ( lyon , france ) and the collegium ramazzini in italy ( 210 ) , we herein present a molecular biology , epidemiological and mathematical modeling reanalysis that strongly disagrees with their conclusion , stating that several cancer types may be caused by random somatic mutations arising during dna replication of normal stem cells . instead of the author 's two - group individualized model , a three - group model is proposed , considerably reducing the fraction of cancer hypothetically attributable to random mutations . the hypothesis that the lifetime risk of cancer differs according to tissue type due to the different total number of divisions of stem cells in normal tissues , is coherent with our knowledge on carcinogenesis , since , according to the somatic mutation theory , cancer is associated with mutations ( 11,12 ) and cell divisions are required for mutations to occur ( 13 ) . however , carcinogenesis is a multistep , multifactorial process , with etiological factors other than the natural proliferative rate of normal tissue ( 14 ) . while random mutations , which may occur in addition to deterministic events during the whole process of carcinogenesis , are well known , this is more problematic when applied to cancer initiation . cancer may result from gene - environment interactions mediated by epigenetic mechanisms ( 15 ) ; thus , in addition to innate or acquired hereditary susceptibility factors , clearly exogenous factors such as chemicals , radiation and/or microorganisms , play a key role in carcinogenesis directly , by interfering with dna , and/or indirectly , through epigenetic pathways ( 1618 ) . moreover , it has been estimated that stochastic mutations , referred to as spontaneous somatic point mutations , may be in the order of 10 to 10 per sexual generation for the entire genome of eukaryotic cells ( 19 ) , and these mutations are not randomly distributed within the eukaryotic genome , but mainly in its non - coding nucleosome - depleted part ( 20 ) . it is unlikely that random mutations at this rate may cause cancer initiation and account for cancer occurrence that is at present significantly more frequent than 1 case out of 1,000 . in fact , as random mutations mainly encompass somatic point mutations rather than cancer - causing ( clonogenic ) driver mutations , and cancer results from several driver mutations ( 15 ) , random mutation - related cancer should be much less frequent yet . we therefore analyzed from the standpoint of epidemiology the authors ' different cancer types in the so called replicative ( r ) stochastic group . 1 , apart from pancreatic cancer , all r group cancers have been shown to be associated with an increased incidence over the last 3 or 4 decades in the usa ( 21 ) , as well as in europe ( 22 ) . we disagree with tomasetti 's response to our question , that  the fact that cancer incidence has increased over the last 34 decades may be explained in part as a consequence of random replicative mutations , given the longer lifespan of the population and that  an increase in screening and awareness certainly played a role in the increase in the observed incidence of melanoma , as well as that of many other cancers. these arguments are not convincing , since cancer may be initiated at the fetal stage ( 23 ) , increased cancer incidence concerns all age categories , and screening by itself can not account for the continuous increased incidence of several cancer types , including those which can not be screened ( 24,25 ) . we therefore concluded that the stochastic interpretation attributed to the author 's r group is not consistent with current epidemiological and biological data . taking into account the supplementary material of the article , we investigated the mathematical method that tomasetti and vogelstein used to define their two groups , r and deterministic ( d ) , the basis of their claim . considering the association between the lifetime cancer risk and the total number of stem cell divisions ( fig . 1a ) , a strong correlation at 0.804 was demonstrated statistically by using the pearson 's chi - square test . however , applying a linear regression test , we obtained a coefficient of determination , denoted r , of only 0.6463 , indicating that a soundly established linear relation is unlikely . moreover , we combined figs . 1 and 2 of the authors article in a single figure for the purpose of simplification and better understanding , and estimated r for each of the arbitrarily individualized r and d groups . we therefore tentatively individualized a third group from the r and d initial groups . as indicated in fig . 2b , we observed a significantly improved linear regression , with r of 0.88 , 0.89 and 0.98 for the newly individualized d , intermediate and r groups , respectively . this suggests that , when restricting the r group to a significantly smaller number of cancer types , the intermediate group may in fact include both stochastic and deterministic events , a hypothesis which appears to be more coherent with what we previously discussed . although a very small proportion of cancers may be caused by spontaneous random mutations , we strongly suggest that the scientific message of tomasetti and vogelstein does not agree with the currently available biological , epidemiological and toxicological data . the process of carcinogenesis has not been sufficiently taken into consideration , so the interpretation of tomasetti 's and vogelstein 's results may be hazardous , as it de - emphasizes highly needed primary prevention and limits it to for a small proportion of cancer types .
a careful molecular biology , epidemiological and mathematical modelling reanalysis of the recently published study titled  cancer etiology . 
 variation in cancer risk among tissues can be explained by the number of stem cell divisions by cristian tomasetti and bert vogelstein , which was published on january 2 , 2015 in the distinguished journal science , led to the conclusion that , contrary to the authors ' claim , many cancer types are not caused by replicative random mutations . rather than the authors ' two arbitrarily individualized groups of cancer , a three - group model 
 is herein proposed in the framework of this technical comment , considerably reducing the fraction of cancer cases hypothetically attributable to random mutations .