Moss - What genes cant do - 2003 (522929), страница 45
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The next question is what might be the relationship of polyp formation to the subsequent stages of carcinogenesisin general, and the acquisition of the ras, DCC, and p53 mutations inparticular? It turns out that this matter becomes best addressed in thecontext of the HNPCC findings, and with some surprising results.HNPCC, as a syndrome, simply reflects the epidemiological observation that there are incidences of elevated levels of colorectal cancer whichdo not involve polyposis but do appear in familial patterns consistentwith Mendelian inheritance.
Only during the last several years did severallines of evidence come together to reveal that the inherited defects werein enzymes associated with the repair of errors in DNA copying. Errorsin copying are most likely where there are regions of DNA with noncoding repetitive sequences. These regions are referred to as microsatellites and the failure to be able to repair errors of microsatellite sequenceduring DNA replication is observed as microsatellite instability (MI).HNPCC was thus shown to involve inherited lesions to mismatch repairgenes (MMR), resulting in cells with microsatellite instability and amutation rate two to three orders of magnitude higher than normalcells.
HNPCC accounts for only 2 to 4 percent of colorectal cancers inWestern countries. Another 13 percent of total colorectal cancers werealso found to have microsatellite instability, and some of these revealsporadic (as opposed to heritble) mutations of the same MME genes.The remaining 85 percent of colorectal cancers do not show microsatellite instability or heightened mutability, and yet they display gross chromosomal losses, with an average loss of 25 percent of randomly selectedalleles. Colorectal cancers thus fall into two distinct categories.
Onegroup displays a heightened rate of mutability and small-scale genomewide sequence errors (MI), but they do not show losses of whole allelesand the other group which does not test positive for increased mutabil-Dialectics of Disorder: Normalization and Pathology as Process179ity and does not show MI but has lost at least 25 percent of its genomicalleles.
At the cytological level, the large-scale loss of alleles is referredto as aneuploidy.Aneuploidy is a common feature of all sorts of cancers at moreadvanced stages of progression. The mechanisms resulting in aneuploidyare not known, but it has generally been treated as a kind of side effectof various aspects of the carcinogenic process as opposed to a specificphysiological state with specific causal significance. Kinzler andVogelstein (1996) are moved to wonder:If aneuploidy were simply the consequence of the neo-plastic factors describedabove [numerous extra cell divisions, abnormal microenvironment, altered physical structure of the cancer cell], it should be found in colorectal tumors withMMR deficiency as often as in other colorectal tumors.This conundrum prompts Kinzler and Vogelstein to utter the followingspeculation which would appear to turn the fundamental presuppositions of the somatic mutation hypothesis on its head:Teleologically, it would thus seem that a cancer needs to develop only one typeof instability and the gross chromosomal changes provide little selective growthadvantage to tumors with mismatch repair deficiency and vice versa.
It wouldalso seem that there are two ways for a tumor to develop the multiple geneticalterations required for malignancy: subtle alterations due to the mismatch repairdeficiency occur in a minority of cases (those with MI), while gross chromosomal alterations occur in the majority.Now whether it is really the intent of Kinzler and Vogelstein to suggestthat the acquisition of gross chromosomal changes is not passivelyobtained but rather the result of active, adaptive processes is not evenpertinent, given that there is no better explanation on the table (whichthey have set). Consider again the initiation of colorectal cancer with theformation of a polyp.
The major problem was how to account for howall the mutations which are required for full-blown cancer could possibly come about, assuming that mutations are passively acquired lowprobability events. But another picture has now presented itself. Perhapsmutability of the cell is physiologically determined as well as a functionof its status in an intercellular field. The polyp already constitutes a kindof disturbed field as did the liver nodule. Neither most nodules nor mostpolyps progress to malignancy, but under certain conditions some do.This progression entails a widespread genomic reorganization brought180Chapter 4about by way of the cell’s own resources, a reorganization (or loss oforganization) which becomes inseparable from the cancer cell’s ability toescape the constraining aspects of the tissue matrix.Further evidence of the active role of a cell in modulating its ownmutability in a disturbed field is provided by Kinzler and Vogelstein inexamining the role of environment in colorectal carcinoma:There is little question about the importance of diet in limiting colorectal cancerincidence in the Western world.
It has been a reasonable assumption that thedietary components responsible were mutagens. However, examination of mutational spectra in colorectal cancers has provided little evidence to favor specificmutagens as causative agents. The most characteristic mutations observed in p53and APC genes, for example, are C-to-T transitions at CG dinucleotides (Harrisand Hollstein, 1993). Such mutations are characteristic of endogenous processesleading to the hydrolytic deamination of methylated C residues in the absenceof mutagen exposure. . .
. Thus, it is possible that the dietary factors which leadto colorectal cancer are not mutagens, but rather irritants that lead to tissueregeneration. Dietary fibers may absorb these irritants, explaining part of theirprotective effect.The logical prediction following from the somatic mutation would bethat mutagens in the gastrointestinal (GI) tract would be the leading environmental factor in promoting-initiating colorectal cancer. The evidencesuggests otherwise, prompting Kinzler and Vogelstein to recover theconcept of an “irritant,” which harkens back to the language of Virchowand company at the end of the nineteenth century when the adaptivecapacity of a cell was still at the center of thinking. Kinzler andVogelstein are unequivocal in the inference they draw from the mutational data: Such mutations are characteristic of endogenous processes.In chapter 3 under the discussion of chromosome marking as an epigenetic inheritance system the point was made that developmental andcontext-sensitive processes by which cells methylate and demethylate theC residue of CpG couplets may play a role in genomic reorganization aswell.
The example of colorectal carcinoma, in which the formation ofan abnormal organizational field (the polyp) may lead to heightenedmutability and eventually widespread loss of heterozygosity, may be justsuch a case.On close consideration it becomes apparent that the upshot of the colorectal multimutation model of carcinogenesis—very much the heir tothe mainstream of the somatic mutation hypothesis—has come to dove-Dialectics of Disorder: Normalization and Pathology as Process181tail with the story that has been told “from the margins” by the likes ofSmithers, Farber, and Rubin. Genetic changes are tantamount to tumorprogression, but the process is hardly unidirectional. Epigenetic systemsof the cell (as discussed in chapter 3) are responsive to the organizationalfield of the cell and in turn influence the state, status, structure, andmutability of DNA. Enzyme-mediated processes are responsible fordeleting, duplicating, amplifying, cutting, pasting and relocating DNAall the time.Cancer is about the protracted disturbance of all of those systems thatstabilize a cell in its developmental compartment.
There are evidentlymany ports of entry when it comes to initiating a disturbance and mostlikely none which are ever in themselves sufficient to dictate an entirecarcinogenic trajectory. Chapter 3 argued that the informational contentof the genome is co-original and reciprocally dependent upon that of theorganizational structure of the cell (on all three levels of its epigeneticinheritance systems). Likewise, so too is the genome and the organizational state of a cell inseparably co-determinative of any abherrent departure from the developmentally stabilized status of a cell. Eitherhydrophobic environmental irritants that become lodged in cell membranes or mutation of cell-adhesion-molecule genes may perturb cell-cellinteractions and cellular fields, which may lead to a stepwise uncoupling of cells from the tissue matrix, progressive destabilization, the reorganization of cellular genomes and ultimately the death of an organism.The metastatic cell that invades a host organ and thus appears to beautonomous is the very late end product of a long, complex, interactive,and highly contingent process.
Similarly, the transformed NIH 3T3 cellin Harry Rubin’s laboratory, which outgrows other colony producers,had its ancestral origins in overcrowded growth conditions in tissueculture. It is hardly a cell whose fate was predetermined and dictatedfrom within its genome. It may be that cancer has many potential portsof entry, albeit with none of them being sufficient to determine a carcinogenic trajectory.8Now here comes the twist. Twentieth-century biology has been guidedlargely by the heuristics of some form of genetic preformationism.Cancer biology, going back to Boveri, has endeavored to explain cancerin terms of the genetics of somatic cells that have sustained mutations182Chapter 4because the epidemiology of human cancer has never been consistentwith the bulk of cancer incidence, being based on the inheritance of agenotype.
Why then, at the end of the twentieth century, when even thepreformationist assumptions of the somatic mutation hypothesis is beingprogressibly undercut, has a genomic model of heritable susceptibility tocancer emerged and even moved onto center stage? Highly touted genetic tests for cancer, such as that developed and marketed by MyriadGenetics for the BRCA1 and BRCA2 genes for breast cancer, have contributed to a public perception that everything turns out to be genetic.Has gene-based heritability proven to play a greater role in the etiology of cancer than previously suspected? Certainly not.
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