Mutation and Cancer: Statistical Study of Retinoblastoma
01 Apr 1971-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 68, Iss: 4, pp 820-823
TL;DR: The hypothesis is developed that retinoblastoma is a cancer caused by two mutational events, in the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells.
Abstract: Based upon observations on 48 cases of retinoblastoma and published reports, the hypothesis is developed that retinoblastoma is a cancer caused by two mutational events. In the dominantly inherited form, one mutation is inherited via the germinal cells and the second occurs in somatic cells. In the nonhereditary form, both mutations occur in somatic cells. The second mutation produces an average of three retinoblastomas per individual inheriting the first mutation. Using Poisson statistics, one can calculate that this number (three) can explain the occasional gene carrier who gets no tumor, those who develop only unilateral tumors, and those who develop bilateral tumors, as well as explaining instances of multiple tumors in one eye. This value for the mean number of tumors occurring in genetic carriers may be used to estimate the mutation rate for each mutation. The germinal and somatic rates for the first, and the somatic rate for the second, mutation, are approximately equal. The germinal mutation may arise in some instances from a delayed mutation.
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TL;DR: Genetic alterations affecting p16INK4a and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development.
Abstract: Uncontrolled cell proliferation is the hallmark of cancer, and tumor cells have typically acquired damage to genes that directly regulate their cell cycles. Genetic alterations affecting p16(INK4a) and cyclin D1, proteins that govern phosphorylation of the retinoblastoma protein (RB) and control exit from the G1 phase of the cell cycle, are so frequent in human cancers that inactivation of this pathway may well be necessary for tumor development. Like the tumor suppressor protein p53, components of this "RB pathway," although not essential for the cell cycle per se, may participate in checkpoint functions that regulate homeostatic tissue renewal throughout life.
5,509 citations
01 Jan 2002
TL;DR: This list includes tumours of undefined neoplastic nature, which are of uncertain differentiation Bone Tumours, Ewing sarcoma/Primitive neuroedtodermal tumour, Myogenic, lipogenic, neural and epithelial tumours, and others.
4,185 citations
01 Jan 2000
TL;DR: This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices, in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation.
Abstract: NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …
3,924 citations
TL;DR: The results suggest that these three DNA viruses may utilize similar mechanisms in transformation and implicate RB binding as a possible step in human papilloma virus-associated carcinogenesis.
Abstract: Deletions or mutations of the retinoblastoma gene, RB1, are common features of many tumors and tumor cell lines. Recently, the RB1 gene product, p105-RB, has been shown to form stable protein/protein complexes with the oncoproteins of two DNA tumor viruses, the adenovirus E1A proteins and the simian virus 40 (SV40) large T antigen. Neither of these viruses is thought to be associated with human cancer, but they can cause tumors in rodents. Binding between the RB anti-oncoprotein and the adenovirus or SV40 oncoprotein can be recapitulated in vitro with coimmunoprecipitation mixing assays. These assays have been used to demonstrate that the E7 oncoprotein of the human papilloma virus type-16 can form similar complexes with p105-RB. Human papilloma virus-16 is found associated with approximately 50 percent of cervical carcinomas. These results suggest that these three DNA viruses may utilize similar mechanisms in transformation and implicate RB binding as a possible step in human papilloma virus-associated carcinogenesis.
2,941 citations
TL;DR: The isolation of a complementary DNA segment that detects a chromosomal segment having the properties of the gene at this locus is described, which is expressed in many tumour types, but no RNA transcript has been found in retinoblastomas and osteosarcomas.
Abstract: The genomes of various tumour cells contain mutant oncogenes that act dominantly, in that their effects can be observed when they are introduced into non-malignant cells. There is evidence for another class of oncogenes, in which tumour-predisposing mutations are recessive to wild-type alleles. Retinoblastoma is a prototype biological model for the study of such recessive oncogenes. This malignant tumour, which arises in the eyes of children, can be explained as the result of two distinct genetic changes, each causing loss of function of one of the two homologous copies at a single genetic locus, Rb, assigned to the q14 band of human chromosome 13. Mutations affecting this locus may be inherited from a parent, may arise during gametogenesis or may occur somatically. Those who inherit a mutant allele at this locus have a high incidence of non-ocular, second tumours, almost half of which are osteosarcomas believed to be caused by the same mutation. Here we describe the isolation of a complementary DNA segment that detects a chromosomal segment having the properties of the gene at this locus. The gene is expressed in many tumour types, but no RNA transcript has been found in retinoblastomas and osteosarcomas. The cDNA fragment detects a locus spanning at least 70 kilobases (kb) in human chromosome band 13q14, all or part of which is frequently deleted in retinoblastomas and osteosarcomas.
2,827 citations
References
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TL;DR: It is postulated that the distribution of the malignant ocular neoplasm most commonly termed retinoblastoma is not at random in human populations, and a disproportionate frequency of both "horizontal" and "vertical" constellations is observed.
Abstract: IT HAS been recognized for many years that the distribution of the malignant ocular neoplasm most commonly termed retinoblastoma is not at random in human populations. Although the great majority of persons with this disease are not known to have any relative similarly affected, there has been observed, considering the rarity of the neoplasm, a disproportionate frequency of both "horizontal" and "vertical" constellations. By the term "horizontal" we refer to the occurrence of two or more affected children in a single sibship, both parents being normal in this respect; by the term "vertical" we refer to an affected parent with one or more affected children. The extensive literature documenting this point has been adequately reviewed elsewhere.1The currently accepted genetic explanation of these findings is largely derived from the papers of Weller,1bGriffith and Sorsby,1cFranceschetti and Bischler,1eand Falls.2In brief, it is postulated
278 citations
TL;DR: An alternative analysis of the observed death rates could be explained on the basis of a " two hit " theory; that only two changes in cell function, the first involving enhancement of the rate of multiplication of cells and the second release from control, were necessary.
Abstract: NORDLING (1953) examined the age specific mortality for cancer of all sites from the published statistics of the United States, the United Kingdom, France and Norway and noted that the tumour death rate rose with the sixth power of the age. He suggested the carcinogenesis might depend on a series of mutations in the affected cells and that the clinical manifestation was dependent on the cumulative effect of this series of mutations. Stocks (1963) examined the mortality rates for gastric cancer in males for a series of cohorts and reached the conclusion that the pattern observed could be explained on the basis that there was a series of 5 mutations and a preclinical development period of about 17 years. Armitage and Doll (1954) made a detailed analysis of the death rates for a number of tumours and showed how the hypothesis of a small number of random discrete changes in cell structure and function could account for the observable steady rise in cancer mortality with age. Three years later (Armitage and Doll, 1957) they published an alternative analysis which suggested that the observed death rates could be explained on the basis of a \" two hit \" theory; that only two changes in cell function, the first involving enhancement ofthe rate of multiplication of cells and the second release from control, were necessary. The relevant mathematical expressions which Armitage and Doll derived were:
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