Ulcerative colitis (UC), a chronic inflammatory condition associated with a
predisposition to colon cancer, is frequently characterized by DNA damage in
the form of microsatellite instability (MSI). A new report links
inflammation in UC with increases in the DNA repair enzymes 3-methyladenine
DNA glycosylase and apurinic/apyrimidinic endonuclease, and, paradoxically,
with increased MSI. These findings may represent a novel mechanism
contributing to MSI in chronic inflammation.


A longstanding question in cancer research is the strong association between
certain chronic inflammatory conditions and the concomitant elevated risk
for malignancy in affected tissues. Understanding the molecular mechanisms
driving the progression to cancer may not only provide more effective means
of prevention but also shed light on mechanisms of carcinogenesis.
Ulcerative colitis (UC), which affects as many as 6 per 100,000 people in
the United States, is a relapsing form of chronic inflammatory disease of
the large bowel. Patients with more than a 10-year history of disease have a
20- to 30-fold greater risk of developing colorectal cancer (1). Both
chromosomal instability (CI) and microsatellite (short, repetitive
nucleotide sequences in DNA) instability (MSI) are present in UC and can be
detected early in dysplastic, premalignant tissues (2, 3). What are the
sources of these changes in DNA sequence? Chromosomal changes are frequent
in cancer and MSI has been clearly documented as a result of mutations in
mismatch repair enzymes in the hereditary nonpolyposis colon cancer
syndrome. MSI is also observed in many other malignancies (4). Accumulation
of mutations in microsatellites could be the result of alterations in
enzymes that normally guarantee DNA stability, thus leading to a mutator
phenotype (4). Existing hypotheses postulate that excess amounts of free
radicals found in inflamed UC tissues overwhelm DNA repair pathways, leading
to the accumulation of damaged DNA (5), or that mismatch repair pathways are
inactivated, either directly by oxidative stress (6) or by hypermethylation
(7). In the traditional view, members of DNA repair pathways are heroic
players, stoically laboring against the overwhelming tide of genetic insults
thrown their way.

"Capt. Rob" wrote in message
ps.com...
Did you have Crohn's disease?


No, but Crohn's killed my mother. I have something more mild and have
been in remission since Thomas was born.

RB