Moss - What genes cant do - 2003 (522929), страница 44
Текст из файла (страница 44)
The Kinzler and Vogelsteinreview is of much interest for a number of reasons. In the previous sectionI have highlighted the distinction between the center, or mainstream, andthe margins or periphery in the history of twentieth-century cancer research, identifying the ongoing effort toward realizing a somaticmutational, and thus subcellular, basis of causation as the mainstream.
By1990, as much attention shifted away from oncogenes to tumor suppressergenes, Bert Vogelstein was already well established as a leader in the fieldby virtue of his work on the p53 tumor suppresser gene. His papers havebeen ranked consistently during the last 10 years among those most frequently cited. Most importantly Vogelstein’s use of human colorectalcancer as the basis for describing a multistep, multimutational progressionhas become the principal exemplar by means of which the somatic mutation model of cancer has come to be understood. There can be little doubtthat Vogelstein’s name is perennially present during the annual deliberations of the Nobel Prize committee.
The Kinzler and Vogelstein reviewappeared in the periodical Cell, a journal that has enjoyed the status ofbeing the most prestigious among molecular biologists for more than 20years. The very fact of having a review article published in Cell is itself anunmistakable indication of high status and recognition. The Kinzler andVogelstein review is thus as mainstream as it gets.Kinzler and Vogelstein set out to detail the role of two rare germ-linemutations in the overall etiology of colorectal carcinogenesis in relationDialectics of Disorder: Normalization and Pathology as Process175to the schemata of sequential mutations, which have become well knownto every student of sporadic cancer.
The article ends with an endorsement of genetic testing for colorectal cancer susceptibility along with anespousal of ethical, legal, and social considerations that need go alongwith it. Kinzler and Vogelstein have thus spanned this distance from thedisciplinary space in which the most heady proclamations of victory overcancer in the 1980s were heard, all the way to the prudently actuarialstance of the 1990s genetic counselor. Why such a strategic retreat? Aclose look at their analysis of the genetics of colorectal cancer, in thecompany of the insights of previous sections, will provide the answer.The key issue will be whether mutations (somatic and/or genomic) aredriving the phenotype, as the somatic-mutation hypothesis must require,or whether in fact the phenotype, understood in terms of cellular behavior and its interactions in a microenvironment, is in fact driving the conditions of mutability of its genome.Colorectal cancer is the most prevalent cause of cancer mortality inthe United States when smoking-related cancers are excluded.
At least50 percent of individuals in the West develop a colorectal cancer by theage of 70, and in about 10 percent of these progression to malignancyensues. Epidemiological studies have identified about 15 percent of colorectal cancer incidence with patterns of dominant inheritance. In classical terms this would suggest that there are certain single genes whichcan cause colorectal cancer in a dominantly acting fashion. Yet manystudies on colorectal cancer by Vogelstein and others have establishedthat at least seven mutations are required.
What has distinguished thecolorectal model in particular is evidence of specificity in the order inwhich these mutations must appear for carcinogenesis to ensue. Therethus appears to be a correlation between certain precancerous stages ofdysplasia and neoplasia with certain mutations that open the door to thenext stage. The sequence has been characterized as follows: The initiator mutation is the APC gene, in which both alleles must be knockedout. This results in the formation of many benign “aberrant crypt foci.”Of these a small number may progress to the early adenoma stage, atwhich time the activation of a single k-ras gene is required for furtherprogression to the intermediate adenoma stage. The late adenoma stageis attained by way of additional mutations on the 18q21 chromosome,176Chapter 4such as that of the DCC gene, again requiring knockouts of both alleles.Finally, the transition to a frank carcinoma is reached by way of the lossof both p53 alleles.
Further progression to invasiveness and beyondwould presumably require additional lesions (Kinzler & Vogelstein1996). The unavoidable problem that a model such as this raises is thatof how so many mutations, each of which is presumably a very low probability event, can possibly occur during a time frame relevant to a humanlife span.
Recent findings on the genetics of familial colorectal cancerprovide additional resources for considering the matter.The two forms of hereditary colorectal disease that have been bestcharacterized are termed FAP and HNPCC (familial adenomatouspolyposis and hereditary nonpolyposis colorectal cancer, respectively).The specifics of these will be examined in order.FAP is the result of the inheritance of a mutation in an APC allele.While germ-line mutations of APC only account for less than 1 percentof colorectal cancers in the United States, FAP does provide a windowonto what has been characterized as the first step in the colorectal carcinogenesis pathway.
Patients with the single germ-line APC mutationtypically develop hundreds to thousands of colorectal polyps by theirsecond and third decades of life. Every colorectal cell of the FAP patientdoes not give rise to a polyp, but rather only about one in a million. Thiswould be consistent with a requirement for a second mutation knockingout the wild-type allele. The effects of the APC mutation are highlytissue-dependent. APC is expressed ubiquitously throughout the body,and yet the mutations are not known to be associated with cancer inother organs. Nor do the same mutations necessarily result in the sameclinical symptoms amongst FAP patients; nor does FAP necessarily leadto colorectal carcinoma, although it certainly increases its probability.
Inthe overall incidence of colorectal carcinoma, the APC mutation has beenthus far identified in about 80 percent of cases. While the ras and p53mutations have been identified as necessary for further progressiontoward full-blown colorectal cancer, neither of these mutations show anycorrelation with colorectal cancer in the absence of an APC mutationalready being present. So it would appear that in the specific context ofcolorectal epithelium (and only there), the APC mutations, while not sufficient for causing cancer, are necessary in the large majority of casesDialectics of Disorder: Normalization and Pathology as Process177(Kinzler & Vogelstein 1996). What then is it that the APC mutations canbe said to cause?The sequence of the APC gene does not provide any clues by way ofanalogy as to the function of the APC protein because it does not showhomology with other genes or proteins that have been characterized.Where inferences with respect to APC function are to be found is withrespect to the binding of the APC protein to other proteins.
The centralthird of APC contains two classes of binding sites for the protein bcatenin. The catenins are cytoplasmic proteins that bind to the family ofcell-adhesion molecules known as cadherins. Evidence suggests thatbinding to b-catenin is necessary for the cadherin to function in bindingadjacent cells together. Given that the binding of b-catenin to cadherinor to APC is mutually exclusive (i.e., competetive) (Kemler 1993), APCmay function to modulate the ability of the colorectal cells to bind toadjacent cells. In addition, the binding state of b-catenin will also affectthe transmission of extracellular signals through the plasma membraneand into the interior of the cell (a process known as signal transduction).What can best be surmised about APC is as follows.
In the absenceof either of the normal alleles a protein is produced which results inthe destabilization of cell-cell interactions in the colorectal epithelium,giving rise to an altered micromorphology known as polyps. The factthat these arise only in colorectal tissue, despite the ubiquitous expression of APC, suggests that it is only in the context of the specificbiochemical-organizational state of differentiated colorectal tissue thatthis sensitivity to the status of the APC molecule can be found. The formation of polyps is a shift in the micro-organizational field of the colorectal tissue in response to a perturbation. In this case the perturbationis a change in cell-cell structure due to the alteration of an internal component which is involved in the architecture of cell-cell adhesion andsignal transmission.
Yet by analogy to the example of liver nodules discussed above, the colorectal polyps may also be a kind of adaptiveresponse to any agent which presents a challenge to local tissue organization, whether this agent is internal and inherent or external in origin.And as in the case of the liver nodules, the colorectal polyps are notthemselves cancerous but are just more prone to becoming so thannormal tissue.178Chapter 4What constitutes then the first step in the direction of colorectal canceris not the APC mutation as such but rather an alteration of the organizational field of the colorectal epithelium into the form of polyps. Asalready stated, it is only in the context of the formation of polyps thatall the subsequent mutations associated with the onset of colorectalcancer are even relevant to it, as there is no correlation otherwise—whichis why the inheritance of FAP is seen to have an apparently direct relationship to colorectal cancer.
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