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The Origin of Point Mutations in Human Tumor Cells1 Bernard S [CANCER RESEARCH 52. 249-253, January 15. 1992] Perspectivesin CancerResearch The Origin of Point Mutations in Human Tumor Cells1 Bernard S. Strauss2 ICRF Clare Hall Laboratories and Department of Molecular Genetics and Cell Biology, The university of Chicago, Chicago, Illinois 6063 7 The idea that point mutation is central to carcinogenesis is zling since one of the major hypotheses of the 1970s was the an old one (e.g. Ref. l). Until recently, however, specific genetic proposal that carcinogens acted to produce point mutations; changes had not been observed in tumors and a keystone of the that all, or at least the overwhelming majority, of carcinogens belief that genetic change is central to carcinogenesis was what were mutagenic; and that the production of mutations was the appeared to be a close correlation between mutagenicity and mechanism by which carcinogens acted (13). The discovery of carcinogenicity (2). The situation is almost completely reversed transforming oncogenes (14), and particularly the observation today. The class of nonmutagenic carcinogens has been shown by Barbacid et al. (15) that methylnitrosourea-induced breast to be considerable (3). On the other hand, so many genetic tumors in rats were invariably associated with G—»Atransitions changes have been observed in individual cancers that the in the ras oncogene of the tumor, appeared to fulfill one of measured mutation rates in somatic cells seem unable to ac Koch's postulates, that an etiological agent should be invariably count for their appearance. For example, single tumors may associated with the development of disease. Identity of the type contain both ras and p53 point mutations along with chromo of mutation produced in experimental tumors by methylnitro- somal changes (4). A recent contribution to this series postu sourea, i.e., G—»Atransitions,with the mutational specificity lates a hypermutability in tumors to account for the multiple observed in vitro (16, 17) lent credence to the hypothesis that mutations observed (5). However, it may be that no special chemically induced tumors resulted, in the first instance, from mechanisms are required but rather that the estimates of mu point mutation in a growth-controlling gene. It was apparent tation rate thus far reported for somatic mammalian cells and even in these investigations that additional factors were in for neutral mutations in the genome do not reflect the rates in volved, since tumors appeared in animals treated with carcino developing tumors. Such measurements most often use Luria- gen only at a particular phase in the estrus cycle (15), but the Delbruck conditions to estimate preexisting mutations. The role of mutagen appeared to be both necessary and clear. unit in which mutation is measured is the cell generation (6). The ras mutations occurred at only a limited number of Such conditions are not applicable to the situation in tumors. positions and it was possible to look for mutations at these Rather, developing tumors are similar to Escherichia coli kept positions by in situ hybridization techniques using synthetic under selective conditions as described by Shapiro (7), by Cairns oligonucleotides (18). Numerous studies of a variety of human et ai. (8), and by Hall (9) in that mutation is time rather than tumors established that ras mutations could be observed, but replication dependent (9, 10) and that it continues in the only in a portion of tumors. Mutation in ras was neither absence of cell proliferation. The mutations observed in bacteria necessary nor sufficient for all tumor development but it did result in a selective advantage, and the particular mutations occur in some tumors. The base changes involved were limited observed in tumors also appear to give the cells in which they to a few codons and their pattern differed in different types of occur a selective advantage. The mechanism by which these tumor (19). time-dependent mutations occur is unknown, but the specificity That carcinogenesis is a complex process has been under of the mutations observed in tumors implies that at least some stood for some time (see Ref. 20 for a general discussion). In are induced as a result of alterations in the DNA. It is not yet experimental systems, the separation of initiation, promotion, clear how the rate of mutation is to be expressed in quiescent and progression fits a simple hypothesis in which initiation cells held under selective conditions. corresponds to the reaction of DNA with an ultimate carcino gen resulting in a mutation which is converted into a tumor by Mutations in Human Cancer promotion and progression. The age dependence of cancer is in agreement with the hypothesis that multiple events, possibly That genomic change, broadly defined, is a part of the trans mutations, are required for the production of a tumor (21) formation of cells to a malignant phenotype is documented by although opinions differ on the precise number involved. Ac many studies establishing the presence of specific chromosomal cording to the view that malignant tumors are due to the changes in particular tumors (11). Translocations and deletions accumulation of multiple genetic changes (22), tumors would as well as aneuploidy accompany the development and progres result after the accumulation of successive (mutational) events. sion of many tumors (4). Specific translocations are character Each event is supposed to be independent. The last event would istic of some carcinogenic transformation (12). Until recently necessarily occur late and would result in a sudden burst of it was not clear that point mutations (the transitions, transver tumors in old age. Estimates of five to seven events fit the age sions, and simple frame-shifts of experimental genetics) were distribution pattern for many tumors, although for retinoblas- also a part of the carcinogenic transformation. This was puz- toma two events suffice (23). The observation of Fearon and Vogelstein (22) of an accumulation of events accompanying the Received 9/3/91; accepted 10/30/91. 1This paper was prepared during the tenure of a Fogarty Senior International development of malignancy in colon tumors fits the multiple Fellowship from the NIH at the ICRF Clare Hall Laboratories. The work from events hypothesis. the author's laboratory was supported by grants from the NIH and the Depart The oncogenes were defined by an experimental protocol ment of Energy. 2To whom requests for reprints should be addressed, at Department of which required these genes to be dominant (14). A second class Molecular Genetics and Cell Biology, The University of Chicago, 920 E. 58th of relevant genes is recessive, participates in tumorigenesis Street, Chicago, IL 60637. when mutant, and presumably protects against tumorigenesis 249 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1992 American Association for Cancer Research. POINT MUTATIONS IN TUMORS when present in the wild type configuration, hence their descrip "generally agreed that mutation rates in mammalian cells occur with a frequency of some 10~5 to 10~6 mutations per cell tion as tumor suppressor genes (24). A wider range of mutations can be detected in such genes, since inactivation can occur by generation" (21). However, it may be that the mutation rates changes at numerous sites, whereas activation of a physiological used for calculation are the wrong rates measured under circum function requires more limited change. The discovery of the stances that are inapplicable to the situation in developing role of the inactivated retinoblastoma gene (25) and of the p53 tumors for reasons presented by Cairns (8) and by Hall (9). The gene (26) has led to a series of studies on the mutations of these mutation rates measured in experimental mammalian systems genes found in human cancers (see references below). The are for selected genes for which "classical" Luria-Delbruck investigations have been made possible by advances in the variance analysis (6) can be used to extract true mutation rates. technology of identifying mutations, particularly by the use of In particular, the rates are measured per cell generation since the polymerase chain reaction which makes determination of it is assumed that this is the appropriate time unit and that the specific mutational change possible without the necessity of mutation requires division. Selection is immediate, in that cells cloning each particular molecule (27). It is this technical devel are plated on media in which they must grow in order to be opment that has made possible the great increase in our knowl scored. [The electrophoretic variants (31) are neutral mutations edge of the mutations present in tumors. The following gener which confer no particular selective advantage.] However, as alizations can be made (a) mutations in p53 can be detected in Cairns (8) and Hall (9) point out, there is another class of tumors of a wide variety of types; (b) in general not all tumors mutations which can be detected when organisms are allowed of a particular type have p53 point mutations (as yet detected); to persist on medium which permits survival but not growth. (c) among those tumors in which p53 mutations are detected, Under these conditions mutations which permit utilization of there is likely to be a loss of heterozygosity, i.e., only the mutant a component in the medium for proliferation can be selected. alíeleofthe gene is detected (22); and (</)the base substitutions These are "normal" point mutations resulting from DNA involved differ in tumors from different sites (28). Although changes but their appearance is time, rather than generation, p53 mutations often occur in tumors, it is unlikely that they dependent. The situation in the progressing prototumor may be analogous to that of the lac or trp~ bacterium on media arise early in tumorigenesis; rather they are late events appar ently related to tumor progression (29). containing lactose as an available carbon source or lacking tryptophan.
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