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Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
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OCR for page 1
1
THE SOMATIC-MUTAT ION THEORY OF CANCER
CHROMOSOMAL ABERRATION
.
In 1914, Boveri26 proposed a link between mutagenesis and
carcinogenesis. But the molecular biology of cancer is still
elusive, and, although mutation is thought to be intimately
connected with cancer, its exact role in the disease cannot be
definitively described. Recent reviews have highlighted the
uncertainty.32~34,5l,67,105,114
Boveri's hypothesis stemmed from his observations on
chromosomal aberrations in tumor cells. Chromosomal
rearrangements continue to be found in some cancers. but no
general pattern has emerged. Klein61 has discussed the
apparent tissue-specific involvement of different chromosomes
in tumor-associated nonrandom karyotype changes. For example,
human B-cell lymphoma is associated with the 14q+ band,
Burkitt's lymphoma with a reciprocal 8:14 translocation, and
myeloid differentiation with changes in chromosomes 22 and 9.
Wiener et al. 119 have described a trisomy-~5 in marine B-cell
lymphoma that suggests a gene duplication on chromosome 15, and
the chromosomal instability associated with Bloom's syndrome is
thought to predispose those afflicted to leukemia and other
cancers. 110 Other examples of chromosomal aberrations assay
elated with neoplasia include a chromosome 3:S translocation
with hereditary renal cell carcinoma, 40 a chromosome 13
de le t i on wi th re t inob las tome, 64 and a de let ion in chromes ome
11 with Wilms' tumor. In a report from the National Wilms'
Tumor Study, Breslow and Beckwith29 suggested that the pro-
portion of Wilms' tumors due to inherited mutation may be sub-
stantially smaller than previously estimated. None of the 20
familial cases had the features associated with genetic
tumors . Al though cytogenet ic analyses were not pe rformed in
this large study, that many familial cases were unilateral and
did not depend on the sub Sects' ages suggested that mechanisms
other than mutation may be responsible for most cases of Wilms'
tumor.
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These findings led Klein,62 Cairns, 34 and Nevers and
Saedler86 to suggest that chromosoma1 rearrangements may be a
gross manifestation of a critical gene-dosage effect. By chro-
mosomal rearrangement, a set of endogenous cancer genes may
come under the influence of more active transcriptional con-
trol . Recent ly , insertion of viral promoters has been shown to
cause transformation in cell cultures by enhanced transcrip-
tion of viral or endogenous oncogenes.3b,91 EndogenOgs5 onc5O-
genes have been mapped on specific human chromosomes, ~
and there is evidence that reciprocal translocations may bring
these genes under different promotional control.62 Thus,
chromosomal rearrangements (observed by using cytogenetic
techniques) and small-ecale transposition events (that can be
detected only genetically) may both produce the same effect.
MOST ULTIMATE CARCINOGENS ARE MUTAGENS
Many chemical carcinogens have been tested for mutagenicity
in the last decade. The development of the Salmonella/micro-
some reverse~mutation assay byAmes and colleagues71~73 sig-
naled the beginning of large-~cale efforts. In combination with
results from other in vitro mutagenicity tests, the Salmo-
nella/microsome assay detects almost all carcinogens with muta-
genic properties. The Committee expressed great confidence in
a small test battery for detecting chemicals with mutagenic
properties.84 The Committee also agreed with other estimates
(e.g., Brusick3~) that approximately 90: of currently known
animal carcinogens are bacterial mutagens.
However, the causal relationship between mutation and
cancer is not as direct as these statistics imply, and the
Committee was reluctant to assert mechanistic links in its
initial report.84 One reason is that some confirmed animal
carcinogens have no mutagenic activity or are mutagenic in only
a minority of the systems in which they are tested. For
example, benzene and arsenic compounds are not mutagenic in the
Salmonella/microsome assay, but do display activity in some
other short-term assays. 2 Phenobarbital, succinic anhy-
dride, and dieldrin are carcinogens that are negative in most
mutagenicity assays.54 The mechanisms by which these came
pounds and some others, such as the steroid hormones (e.g.,
175-estradiol), cause cancer are not known. Rubinl05 has
stressed the difficulty in ascribing mutational mechanisms to
cancers caused by a variety of nongenetic agents.
Cairns34 has proposed that transposons may constitute
major mechanism in the development of cancer and has urged
examination of agents that increase the frequency of trans-
positions. Many of these agents would not be detected in
conventional in vitro mutagenicity assays, especially if
eukaryotic and bacterial transposons behaved differently.
2
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Fahmy and Fahmy45,46 have begun studies on the chemical
induction of transposition with the white (w+) eye-color gene
complex of Drosophila. Stable and nonstable genetic features
of the ~ omplex are used to assess germinal mutation and somatic
gene expression that results from transposition of a duplicate
regulatory locus in w+. Preliminary evidence derived from
the few carcinogens tested suggests that mutagenic carcinogens
have an influence on supposed transpositions, but this phenol
enon is unrelated to a carcinogen's mutagenic potency. Further
work is required to confirm and extend these findings. Eeken
and Sobels44 have studied chemically induced transposition at
the singed bristle (en) locus of Drosophila. Powerful muta-
gens, such as ethyl nitrosourea and methyl methanesulfonate,
did not greatly influence reversion of insertion mutation, but
DNA-repair defects (measured in the repair-deficient strain
me i-9 /me i-4 1) did inte rfere .
Although not all mutagenicity test data are in concordance
with carcinogenicity data, most investigators believe that a
relationship exists between mutagenesis and cancer. In addi-
tion to the high correlation between short-term mutagenicity
and animal chemical-carcinogenicity data, there is experimental
support for the multistage model of carcinogenesis. Recent
reviews53~65~80 have agreed that somatic mutation is likely
to be the leading cause of initiation of the carcinogenic
process.
Berenblum and Shubik23 provided early evidence of a
mutational mechanism in the initiation of cancer. Recently
gathered evidence indicates that, in later stages of progres-
sion to malignancy (i.e., promotion), DNA may be unaf-
fected.22~69 However, as Cairns has pointed out,33 pro-
motional activity that produces cell proliferation can be
accommodated in a multistage cancer model in which the first
stage derives from somatic mutation. Other new data also
reflect the mutational etiology of cancer. Weinberg et
al.ll6 and Barbacid et al.l°l have provided evidence that a
single point mutation in the coding region of a human bladder
proto-oncogene may be sufficient for its conversion to an on c'
gene that elicits a carcinoma. Although this finding awaits
additional documentation, 7~81 it offers some support for
mutation as an early part of the care inogenic process .
ULTIMATE CARCINOGENS THAT ARE NOT MUTAGENS
From a regulatory standpoint, it is important to be aware
of a set of potent human or animal carcinogens with no observed
or only inconclus ive mutagenic activity. Human exposure to
many of these chemicals may be quite high. This phenomenon has
created concern over the protection afforded by mutagenicity
tests in predicting carcinogenic potential, because many of
5
3
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tines e substances are present in the environment at high concen-
trations. Consequently, as Squirell2 emphasized, carcino-
genicity testing in laboratory animals remains the primary
basis for most regulatory decisions. Because no specific
experimental factor accurately predicts human carcinogenicity,
Squire proposed ranking potential carcinogens according to
several factors, including genotoxicity tests.
There are two principal reasons why some chemical carcin-
ogens are not detected in mutagenicity tests. The first is
obvious : several chemicals (e.g., steroid hormones) either
cause cancer by nongenotoxic means or alter DNA indirectly;
these chemicals do not appear to be mutagens under any con-
ditions. The second reason is that mutagenicity tests are
inef ficient because of inadequate permeability, insensitivity
of genetic end points, metabolic inadequacy, or other factors.
To counter weaknesses of individual tests, the phylogenetic
range of test batteries is broad and the sources of metabolic
activation are varied. Thus, the probability is low that, if a
battery of short-term tests were used, a confirmed genotoxic
carcinogen could be legitimately shown to be nonmutagenic.
GENETICS OF CANCER
Investigators have approached the genetic etiology of
cancer in several ways. One approach is experimental. Another
involves the study of the inheritance of cancer in human popu-
lations and the ef fects of genetic disturbances in select
populations. A third combines epidemiologic and experimental
approaches in in vitro experiments with cells from human tumors
that are known to be or suspected of being inherited geneti-
cally. The outcome of such approaches will be a description of
the inheritance of cancer and an understanding of the mechanism
respons ible .
Cancer occurs in a few genetic syndromes,63~65 and it is
not unreasonable to assume a genetic basis for predisposition
to the disease. However, a more obvious hereditary pattern of
human carcinogenesis has not been found. Perhaps the lack of
such a pattern is due to the multiple stages of the disease,
each of which might require the action of separate genes.
Perhaps cancer results from a polygenic trait in many cases.
In lieu of strict simple Mendelian inheritance, the human popu-
lation appears to be heterogeneous in its Susceptibility to
neoplasia. "Susceptibility" may involve a genetically influ-
enced lace-in-life change (i.e., like graying of hair) ; in sus-
ceptible persons, this change occurs earlier in life than it
does in less susceptible persons.
Studies of human cell transformation in vitro reflect
efforts to understand the mutational basis of carcinogenesis.
Barrett and colleaguesi5~6 have shown that diethylstil-
4
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bestro! (DES) induced neoplastic and morphologic transformation
at a frequency similar to that of benzota~pyrene. However, DES
failed to induce somatic mutation at two genetic loci, whereas
benzota~pyrene was mutagenic. Thus, two independent mechanisms
appeared to lead to the same effect. In a review of the liter-
ature, Parodi and Brambilla 7 claimed that transformation
occurs 100-1,000 times more frequently than Mutation at a
defined concentration of chemical. Strausll asserted that
the range of difference is one-tenth as great and pointed out
the technical difficulties in comparing the two end points in
divergent test systems. Using mammalian cells in culture,
Iluberman57 studied mutagenesis at the ouabain focus and cell
transformation and concluded that approximately 20 genes may be
involved in one transformation event.
Cell hybridomas produced by cell fusion provide another in
vitro system for examining mutationally induced transfor-
mation. Harris has discussed the heritability of malignancy on
the basis of hybridoma data, 51 especially in the context of
the phenomenon of chromosomal exclusion and tumorigenicity. He
concluded that Mendelian segregation patterns of hybrid cells
do not favor a truly dominant or recessive mode.
Harpists conclusion was supported by the more recent
analysis of Sabin.1 6 The suppression of malignancy by cell
fusion and subsequent chromosomal loss also is stable and
transmissible in some cases. However, the data are often
inconsistent. For example, malignancy can be suppressed in
natural ly occurring human cancers by fus ion of cancer cel Is to
normal human fibroblasts, differentiating epithelial keratino-
cytes, and cancer cells of different somatic cell origin. But
suppression has not yet been specifically linked either with a
cancer cell of a particular origin or with a type of non-
malignant cell to which the cancer cell is fused. Attempts to
correlate suppression with the segregation of specific chromo-
somes, even for tissue-specific neoplasia, have also been
inconsistent. Although the retention of specific chromosomes
and the suppression of the malignant phenotypes imply a
dominant mechanism, in vitro data cannot yet properly
distinguish a definitive segregation pattern.
Analysis of human populations indicates strongly that sus-
ceptibility to cancer varies among individuals and that genetic
predisposition may be more important for the development of
~ ome tumors than others .63 Moolga~kar and Knudson argued
that the development of hereditary tumors should not be over-
looked on the grounds that they represent only a small fraction
of all cancers; rather, they offer an opportunity to study the
multistage process of care inogenesis.
Mendelian analysis shows that almost all heredi~cary cancers
segregate in an autosomal dominant fashion. Assuming the
relationship to be strict, Moolgavkar and Knudson8O consented
that. "even though every cell in a susceptible tissue carries
5
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the cancer gene, only a few of the cells go on to become
malignant, which indicates that inheritance of the gene is not
sufficient (at the cellular level) and that at least one other
event is necessary fot malignant transformation. " In a two-
stage cancer model, the other event i,7not necessarily
mutation. Among many others, Clayton has discussed non-
genetic mechanisms for the second stage of a two-stage cancer
model. Enhanced cellular proliferation has been identified as
a possible participant in producing tumors.
Examples of autosomal dominant cancers are bilateral
retinoblastoma, neuroblastoma Wilms' tumor, and some carci-
nomas of the colon. McKusick}6 listed approximately 30 human
cancers that may be inherited in a dominant fashion. These
account for approximately I: of all human cancers in the United
States.63 The total number of human cancer genes remains a
matter of speculation; Moolgavkar and Knudson 0 suggested
that there may be 100-200, whereas recent hybridization data
between viral or human oncogenes and human DNA imply a range of
only 10-20.25 However, the sensitivity of nucleic acid
hybridization techniques is probably not so great that all
cancer genes can be detected definitively.
The even rarer recessively inherited cancers are important
in unders tending mechanisms . Two disorders, xeroderma
pigmentosum (XP) and ataxia telangiectasia, occur in persons
severely deficient in DNA repair; the deficiency probably
increases their disposition to cancer. Persone with two other
genetic syndromes, Fanconi's anemia and Bloom's syndrome,
exhibit several abnormalities, including chromosomal gaps and
DNA strand-breaking. By implication, these recessive disorders
are linked mechanistically to increased cancer inc idence .
Again, however, the relationship demands scrutiny. Cairns34
argued that XP patients have a greater frequency of cancer only
of the skin, where W-light-induced damage can occur. He
asserted that exposure to other mutagens does not increase the
incidence of other cancers beyond that in the general popula-
tion. This anomaly cannot be easily explained, and a possible
conclusion is that the cancers are not caused by the type of
DNA damage that XP patients are unable to repair. However, the
limited number of XP patients in these studies reduces the
certainty of epidemiologic data. Indeed, some evidence sum
Bests that an excess of cancers exists in XP patients in sites
other than the skin .66
Garner and Hertzog48 proposed the counterargument that
XP patients shoult not, a priori, be expected to have a higher
incidence of internal cancers. Organ-specific metabolism, DNA
repair, and resistance to dimes and other lesions like those
induced by W may influence tumor formation.
Peto9 has recently investigated the idea that there are
dif ferent individual susceptibilities to cancer. From
epidemiologic analyses, he set up three broad classes. The
6
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first includes cases in which the increase in risk is more than
a factor of 1,000. Cancers included in this group are
bilateral retinoblastomas and the squamous cell skin cancers of
XP patients. Although some pi rsone are at tremendous risk,
only a minute fraction of human cancers are in this category.
The second category includes cancers for which a genetic
predispos ition leads to risks approximately 10-100 times higher
than that in the general populat ion. Pe to argued that cancers
in this group may account for a substantial proportion of all
cancers, but their categorization by frequency may be very
difficult to prove. He argued further that the relative risk
in relatives of patients compared with the general population
may be an order of magnitude lee ~ than the relative risk in
suspectible persons compared with nonsusceptible persons. He
gave three reasons for this: not all cancer patients are
susceptible, even fewer relatives are susceptible, and the
general population contains susceptible and nonsusceptible
persons. Peto surmised that a third category is composed of
persons whos e gene t ic risk is increased by les ~ than a factor
of 10 and who may remain undetected in the population.
7
Representative terms from entire chapter:
human cancers
