Genomic instability --- also called "genetic
instability" and "chromosomal instability" --- refers to
abnormally high rates (possibly accelerating rates) of genetic
change occurring serially and spontaneously in
cell-populations, as they descend from the same ancestral
cell. By contrast, normal cells maintain genomic stability by
operation of elaborate systems which ensure accurate
duplication and distribution of DNA to progeny-cells
(Cheng 1993, p.124), and which prevent
duplication of genetically abnormal cells. These systems
("metabolic pathways") involve an estimated 100 genes
(Cheng 1993, p.142).
Why is genomic instability so important? Many (not
all) cancer biologists now believe that genomic instability
"not only initiates carcinogenesis, but also allows the tumor
cell to become metastatic and evade drug
toxicity" (Tlsty
1993, p.645), and "The loss of stability of the genome is
becoming accepted as one of the most important aspects of
carcinogenesis" (Morgan 1996,
p.247), and "One of the
hallmarks of the cancer cell is the inherent instability of
its genome" (Morgan 1996, p.254).
Although these observations are far from new, they
certainly did not receive the attention they merit until
recently.
>>>>> GLOSSARY <<<<<
Part 1
A Deep Insight from 1914, Slowly Confirmed
It was the year 1956 when the normal number of human
chromosomes per cell was firmly established as 46. Soon
thereafter, it became clear that cells of advanced cancers
have often evolved an abnormal number of chromosomes
("aneuploidy").
Such observations were consistent with the prediction
of Theodor Boveri (Boveri
1914), a great German embryologist
who postulated that malignancy is the result of inappropriate
balance of instructions (genetic information) in the tumor
cells. Such "imbalance" can result not only from numerical
chromosome aberrations, but also from structural alterations
within the 46 chromosomes. As a leading cause of structural
chromosome aberrations (deletions, acentric fragments,
translocations, inversions, dicentrics, etc.), ionizing
radiation is well-established.
When my colleagues and I (JWG) initiated a research
program in 1963 (at the Atomic Energy Commission's Livermore
National Laboratory), to test Boveri's hypothesis, there was
very little interest in the concept. Although the techniques
for detecting structural chromosome aberrations were extremely
crude then, compared with current techniques, we were making
gradual progress (Minkler 1970, +
Minkler 1971). However, the Atomic Energy
Commission became angry with me after
a paper I presented at an IEEE Symposium
(Gofman 1969), and canceled our
funding in the early 1970s (Seaborg 1993, Chapter 8,
"Challenge from Within," + Terkel 1995, pp.406-408).
In October 1976, the journal Science published Peter
C. Nowell's classic paper entitled, "The Clonal Evolution of
Tumor Cell Populations" --- a paper almost always cited by
today's analysts of genomic instability. Among other things,
Nowell's 1976 paper discussed evidence, from various analysts,
indicating that as tumor cells become increasingly aneuploid,
the malignancy becomes increasingly aggressive (Nowell,
p.25). Reasoning from the available evidence at that time,
Nowell proposed the following model of multi-step
carcinogenesis:
Tumor initiation occurs by an induced change in a
single, previously normal cell, which makes the cell
"neoplastic" (partially liberated from normal growth controls)
and provides the cell with a selective growth advantage over
adjacent normal cells (Nowell, p.23).
"From time to time, as a result of genetic instability
in the expanding tumor population, mutant cells are produced
... Nearly all of these variants are eliminated, because of
metabolic disadvantage or immunologic destruction ... but
occasionally one has an additional selective advantage with
respect to the original tumor cells as well as normal cells,
and this mutant becomes the precursor of a new predominant
subpopulation" (Nowell, p.23). And:
"Over time, there is sequential selection by an
evolutionary process of sub-lines which are increasingly
abnormal, both genetically and biologically ... Ultimately,
the fully developed malignancy as it appears clinically has a
unique, aneuploid karyotype associated with aberrant metabolic
behavior and specific antigenic properties, and it also has
the capability of continued variation as long as the tumor
persists" (Nowell, p.23). And:
"The major contention of this article is that the
biological events recognized in tumor progression represent
(i) the effects of acquired genetic instability in the
neoplastic cells, and (ii) the sequential selection of variant
subpopulations produced as a result of that genetic
instability" (Nowell, p.25).
The recent surge of interest in genomic instability
reflects the recognition that the cancer process represents a
trip (or set of trips) from the stable genome to the genome
with diverse deviations. It has been a long wait for Boveri.
Part 2
Ionizing Radiation as a Cause of Genomic Instability
Today, laboratory researchers are performing
reality-checks on this logic: Genomic instability can be
initiated and intensified by any type of genetic mutation
(including chromosome aberrations), when such mutation alters
some of the DNA which maintains genomic stability. Of course,
such DNA includes the numerous DNA segments which govern DNA
synthesis, cell-division, and also the routine repair of the
genome --- the "repair genes" (Cheng 1993,
p.131; Morgan 1996,
p.248).
When a mutagen has induced genomic instability in a
cell, some of the cell's descendants will experience new and
unrepaired genetic abnormalities at an excessive rate, even
though the descendants themselves received no exposure to the
mutagen used in the experiment. This occurs because such
cells have inherited a genome which was injured with respect
to maintaining genomic stability.
Very recently, a technique has been developed for
efficiently detecting three of the types of chromosome
aberrations which are very prominent in genomic instability:
Aneuploidy (wrong number of chromosomes), deletions (permanent
removal of DNA segments, long or short), and
gene-amplifications (extra copies of specific DNA segments).
This technique, called Comparative Genomic Hybridization, was
first described by Kallioniemi (1992, in
Science). However, such a technique does not
detect many other kinds of mutations.
The nature of the genetic code is such that mutations
need not be gross in order to have gross biological
consequences. For instance, permanent removal of a single
nucleotide (a micro-deletion) can totally garble much of a
gene's code, by causing what is called a "frame-shift." Then
this non-functional gene can be the phenomenon which wrecks
part of the system which would otherwise maintain genetic
stability.
Amplification (instead of injury), of the crucial
genes in the stability-system, also can permit a cell to
escape the controls which otherwise prevent duplication of
cells with injured genomes. Evidence is developing that gene
amplification is associated with dicentric chromosomes and
circular acentric fragments called "double minutes"
(DiLeonardo 1993, p.656) --- very
well-known products among the consequences of ionizing radiation.
The sequence, in which various mutations accumulate in
tumor cells, may or may not matter. "For example, one or more
pre-cancerous mutations might lie dormant until additional
mutations create an environment in which the prior changes
confer a selective advantage" (DiLeonardo
1993, p.655, citing Kemp 1993, +
Fearon 1990, + Temin 1988).
The fact, that ionizing radiation is a mutagen capable
of causing all known types of genetic mutation --- from micro
to gross, at any DNA location along any chromosome --- made it
utterly predictable that ionizing radiation would be a cause
of genomic instability. Indeed, one of the last projects
completed by our research group at the Livermore Lab, before
the Atomic Energy Commission shut down our work, was a
demonstration which showed that ionizing radiation can induce
genomic instability. Our experiments used gamma rays and
cultured human fibroblasts (Minkler 1971).
During recent years, multiple experiments have
confirmed the fact that ionizing radiation can cause genomic
instability. Such results have been observed after both
low-LET radiation (such as xrays and gamma rays) and high-LET
radiation (such as alpha particles). Among numerous papers,
see, for instance:
- Kadhim 1992;
- Holmberg 1993 (who cites Minkler 1971);
- Marder 1993 (especially p.6674);
- Mendonca 1993;
- Kadhim 1994;
- Kronenberg 1994 (radiation dose-response, p.605);
- Kadhim 1995;
- Morgan 1996 (review).
In the mass media, some writers have expressed
astonishment that radiation-induced genomic instability is not
detected until several cell-divisions have occurred after the
radiation exposure. They seem to imagine that the delay
reflects a mysterious discontinuity between cause and effect.
There is no discontinuity, of course --- a point made
explicitly in Kadhim 1992 (p.739). With
current techniques, and with uncertainties about where to search
closely among a billion nucleotides, it is just not possible to
detect every intermediate step.
Part 3
Implications: Curing vs. Preventing Cancer
The induction of genomic instability in a cell does
not guarantee that it will become malignant. Genomic
instability increases the rate of mutation in that cell and
its descendants, and with this higher rate, the cells each
have a higher probability that at least one of them will
accumulate all the genetic powers of a killer-cancer. These
powers include the ability to thrive better than normal cells,
to invade inappropriate tissue, to adapt to the new conditions
there, to recruit a blood supply, to fool the immune system,
and many other properties.
No one claims, yet, that genomic instability must
precede every case of cancer. However, genomic instability
helps to explain why cancer is sometimes called "at least a
hundred different diseases." Indeed, genomic instability
means that each case of cancer may develop a genome like no
other case. Is it any wonder that individual tumors often
differ in behavior from each other?
Nowell's 1976 paper was certainly not the
last one to observe that cancers become increasingly deviant in their
genomes, as they "advance." Tlsty 1993
(p.645) cites several more recent papers. Near the end of his paper,
Nowell wrote (p.27):
"The fact that most human malignancies are aneuploid
and individual in their cytogenetic alterations is somewhat
discouraging with respect to therapeutic considerations ...
With variants being continually produced, and even increasing
in frequency with tumor progression, the neoplasm possesses a
marked capacity for generating mutant sub-lines, resistant to
whatever therapeutic modality the physician introduces ... The
same capacity for variation and selection which permitted the
evolution of a malignant population [of cells] from the
original aberrant cell, also provides the opportunity for the
tumor to adapt successfully to the inimical environment of
therapy, to the detriment of the patient."
And Some Lessons:
(A)
Genomic instability will probably keep cancer hard
to cure.
(B)
The quickest path to less cancer-misery in the
future would be a policy of reducing exposure to carcinogens.
(C)
Ionizing radiation is almost certainly the most
potent carcinogen to which vast numbers of people are actually
exposed (see Part 4).
Part 4
Five Key Facts and Three Restrained Comments
(1)
Ionizing radiation is a mutagen having special
properties which make some radiation-induced genetic injuries
complex and impossible for a cell to repair correctly ---
quite unlike the routine damage from endogenous free radicals
(Ward 1988, + Gofman
1990, Chapter 18,
Part 2, +
Ward 1991, +
Baverstock 1991, +
Ward 1995, +
Gofman 1997).
(2)
Ionizing radiation is a mutagen which undeniably
can cause every known kind of mutation, at any DNA location
along any chromosome. The body does not always eliminate
cells having harmful mutations. If it did, there would be no
cancer or inherited afflictions.
(3)
Ionizing radiation is a mutagen known to induce
genomic instability (references provided in earlier sections).
(4)
Ionizing radiation is a human carcinogen at every
dose-level, not just at high doses; there is no threshold
dose. A single photon or a single high-speed particle can
cause unrepairable genetic damage. (See Gofman
1990, Chapters 18-21,
+ UNSCEAR 1993, Annex F, especially p.636
para.84, p.680 para.323, + NRPB 1995,
especially pp.59-61, p.68, p.75, + Pierce
1996, p.9, + Gofman 1996,
Chapter 45, +
Riches 1997, p.519, +
Hei 1997).
(5)
Ionizing radiation is a mutagen observed to induce virtually every
kind of human cancer (Gofman 1969, p.4,
+ BEIR 1980, Section 5, +
UNSCEAR 1988, p.460 para.394).
And the Comments:
(1)
In view of all the five facts above, it would be
inappropriate to doubt the menace of low-dose ionizing
radiation.
(2)
And in view of all the five facts, it is strange
--- in studies which attempt to explain a difference in
cancer-rates between two groups --- that the question is so
seldom asked: How do the radiation histories differ between
the groups? In view of the five facts above, it should be the
first question.
(3)
And in view of the five facts, it is sad that so many members
of the medical profession give only lip-service to the need to
reduce the unnecessarily high exposures to radiation administered
by their own profession (UNSCEAR 1993,
Annex C, + Gofman 1996,
Chapter 48). Today, the two largest
sources of voluntary radiation exposure are (i) pre-cancer
medical procedures, including CT scans and fluoroscopy
(NCRP 1987, p.59, +
NCRP 1989, p.69) and
(ii) cigarette-smoking --- which delivers appreciable
alpha-particle radiation to the lungs (Martell
1974, 1975,
1983, + NCRP 1984,
+ BEIR 1990, p.19). As for involuntary
exposures accumulated from nuclear pollution, they have been
poorly ascertained --- to put it in a kindly fashion.
# # # # #
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# # # # #
Committee for Nuclear Responsibiity, Inc. (CNR)
POB 421993, San Francisco, CA 94142, USA
Internet http://www.ratical.org/radiation/CNR/
An educational group since 1971.
We thank David T. Ratcliffe for his most generous and
talented work in placing CNR publications on the Internet at
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