[Date Prev][Date Next][Thread Prev][Thread Next][Date Index][Thread Index]
Another article: cancer is an accumulation of failure of repair
Group,
The following article in today's New York Times, reports on a paper in the Aug
15 Science. It states:
"When BRCA1 is defective, it is unable to repair oxidative DNA damage,
the most common insult to the genetic material of cells throughout the body."
"An accumulation of genetic damage to the DNA is how overexposure to
sunlight can cause skin cancer and an overdose of radiation from X-rays can
cause cancer in internal tissues like the thyroid gland. When oxidative damage
occurs in genes that determine cell growth and when the mechanism that
normally repairs such damage fails to work properly, the cell is no longer
able to keep its growth in check and a malignant tumor results."
The fact of oxidative DNA damage and repair, and the role of failed or
overwhelmed repair mechanisms as the cause of cancer, continues to
dramatically accumulate. The idea that an incidental "hit" by radiation is a
stochastic event that can lead to cancer, with average background radiation
DNA damage events causing 10 million times fewer damage events than normal
oxidative metabolism (with 30,000 damaged DNA in each cell at any time, being
repaired at repair half time of 5 to 45 minutes), is further recognized as a
false foundation in the biology of cancer.
With the evidence of stimulation of repair mechanisms by low-dose radiation,
the biological basis for beneficial effects (e.g., the reduction in breast
cancer in the Canadian fluoroscopy study at low dose rates, vs the inceases in
high-dose exposures, along with the massive literature on the evidence of such
biological and health effects, that were dismissed as "anomalies') is becoming
increasingly grounded and undeniable in hard data.
I would appreciate any comments on the Science article by those who review it.
Thanks.
Regards, Jim Muckerheide
========================
New York Times: August 14, 1998
Study Finds How Gene's Defects Cause Breast Cancer
By JANE E. BRODY
Scientists at the University of North Carolina have
made an important discovery about how defects in one
of the two breast cancer genes, BRCA1, raise the risk of
the disease: They leave cells without the normal ability
to correct certain mistakes that commonly occur in their
genetic machinery.
Scientists and experts elsewhere say the finding has
potentially important clinical implications for people
known to carry the defective gene in their cells. On the
one hand, it could result in more effective treatments
for hereditary breast cancer. It could also lead to a
test that would predict which of the women and men who
carry the defective gene are most likely to develop
cancer.
On the other hand, the new understanding raises
questions about the safety of starting at a young age to
do regular mammograms in women who inherit the defective
gene.
The new information, reported in Friday's issue of the
journal Science, will add to the understanding of how
cancer starts and what might be done to prevent it. The
lead author of the study, Lori Gwen, a graduate student,
said, "This is the first direct evidence of a function
for this tumor-suppressor gene, and it helps to explain
how the gene may be involved in cancer."
The study, done in specially altered cells derived from
a mouse, showed that the BRCA1 gene directly or
indirectly participates in a process called
transcription-coupled repair, a rapid means of
correcting mistakes that occur in the DNA of other
genes.
When people make a mistake writing with a pencil, they
use an eraser, on the typewriter they use white-out and
on the computer, the delete button. When an error occurs
in the DNA of a gene, cells rely on an error-specific
repair mechanism to knock out the errant information.
In Friday's report, Ms. Gowen, Dr. Steven Leadon and
colleagues report that the normal task of BRCA1, one of
the two genes known to be involved in hereditary cancers
of the breast and ovary, is to repair DNA damage caused
by oxidation, a process that occurs continually in the
body in the course of normal metabolism and that can
also result from exposure to outside agents like
radiation.
When BRCA1 is defective, it is unable to repair
oxidative DNA damage, the most common insult to the
genetic material of cells throughout the body. A
defective BRCA1 gene is responsible for about 5 percent
of all breast cancers and can affect men as well as
women in families with hereditary breast cancer.
An accumulation of genetic damage to the DNA is how
overexposure to sunlight can cause skin cancer and an
overdose of radiation from X-rays can cause cancer in
internal tissues like the thyroid gland. When oxidative
damage occurs in genes that determine cell growth and
when the mechanism that normally repairs such damage
fails to work properly, the cell is no longer able to
keep its growth in check and a malignant tumor results.
There are already several other cancers that have been
linked to genes that have lost their ability to repair
defective DNA. Skin cancers commonly occur in people
with the rare hereditary disorder, xeroderma
pigmentosum, after exposure to sunlight. Another is a
rare hereditary form of colon cancer, hereditary
nonpolyposis colon cancer, or Lynch syndrome, in which a
defective repair gene fails to correct a mismatch in the
DNA.
Dr. Bert Vogelstein, a cancer geneticist at Johns
Hopkins University who unraveled the defect involved in
the colon cancer gene, said that someone who carried a
defective BRCA gene started out with both a normal and a
defective version of the gene in each cell. But when a
particular mutation occurs in the normal BRCA gene in
breast or ovarian tissue, the pace of DNA repair changes
from that of a sprint to a slow crawl. This allows
mistakes to accumulate that may eventually result in the
uncontrolled growth of a tumor.
But Vogelstein also suggested that an inability to
rapidly repair oxidative damage might prove to be a
tumor's Achilles heel and lead to new improved
therapies. The defect suggests, he said, that these
tumors "are likely to be extremely sensitive" to
therapeutic radiation or to chemotherapy drugs that
cause oxidative damage. Tumor cells would be hit harder
by such treatment than normal cells, which would still
have one normal copy of the BRCA gene that could correct
oxidative damage induced by the therapy.
Leadon, a molecular biologist who studies how damaged
DNA is repaired, suggested another benefit: the
possibility of determining who has a defect in BRCA1
that "would lead to an inability to carry out oxidative
repair." He said that "BRCA1 is a very large gene that
probably has multiple functions and can have mutations
that are not important." Leadon added that the new
finding "will help us determine which mutations are
important," which could eventually lead to a test that
revealed who would be most likely to get cancer.
But Dr. Henry Lynch, an oncologist and expert on
hereditary cancers at Creighton University in Omaha,
Neb., suggested that the new finding could prove to be
"a double-edged sword of Damocles." Lynch said that if a
woman known to carry one defective BRCA1 gene was
subjected to repeated mammograms, say, starting at the
age of 25, the X-rays would help detect an early, more
curable breast cancer, but at the same time the
cumulative exposure to radiation might increase her risk
of developing a cancer.
************************************************************************
The RADSAFE Frequently Asked Questions list, archives and subscription
information can be accessed at http://www.ehs.uiuc.edu/~rad/radsafe.html