(Loss of DNA repair capacity due to inactivation of a specific gene
is one of the characteristics of cancer, and can already be detected
in normal appearing tissues away from the from the cancer)

Contact: Sarah L. Zielinski
jncimedia@...
301-841-1287
Journal of the National Cancer Institute

Change in gene may be underlying molecular defect in some colorectal
cancers, study suggests
Inactivation of a DNA repair gene may be an early step in the
development of sporadic colorectal tumors, and detection of the
molecular basis for this inactivation may ultimately be useful in
risk assessment for colorectal cancer, according to a new study in
the September 21 issue of the Journal of the National Cancer
Institute.
Cancers can arise from a region of cells with a "field defect", cells
that appear normal but that have an underlying molecular defect. The
molecular basis for the field defect is easy to understand when
tumors develop from cells that all have similar genetic
abnormalities, such as those that occur in patients who are
genetically predisposed to a cancer or those who undergo an exposure
to a carcinogen such as tobacco smoke. However, how the field defect
may arise in most sporadic cancers in unclear.

In colorectal cancer, the DNA repair gene O6-methylguanine-DNA
methyltransferase (MGMT) is often methylated--that is, the gene's
promoter region has methyl groups added to it, which inactivate the
gene. Jean-Pierre J. Issa, M.D., of the University of Texas M. D.
Anderson Cancer Center in Houston, and colleagues hypothesized that
MGMT promoter methylation could be one of the characteristics of the
field defect in colorectal cancer, so they studied MGMT promoter
methylation in the tumor, adjacent mucosa, and nonadjacent mucosa of
95 colorectal cancer patients and in the colon mucosa of 33 subjects
without cancer.

MGMT promoter methylation was found in 50% to 94% of colorectal
tumors, depending on the method of detection, and normal-appearing
colon mucosa up to 10 cm away from the tumor had detectable MGMT
methylation. In addition, the authors detected MGMT methylation in
the normal colon mucosa of several subjects who did not have cancer.

"Because a loss of MGMT protein function is a plausible predisposing
factor for cancer through the increased occurrence of mutations…, our
data indicate that MGMT promoter methylation may qualify as a marker
of the field defect in colorectal cancer," the authors write. In
addition, "given the high lifetime risk of colorectal tumor
development in the U.S. population, it is reasonable to propose
testing to determine whether healthy persons with MGMT promoter
methylation in normal colorectal mucosa are at higher risk of
developing a colon tumor than those without such methylation."

In an editorial, Edward Giovannucci, M.D., Sc.D., of the Harvard
School of Public Health, and Shuji Ogino, of Brigham and Women's
Hospital, both in Boston, review the concept of the field defect
(also called the field effect or field cancerization). They also
raise several questions about how these findings may affect related
areas of research, such as approaches to chemoprevention and "whether
the reversal of DNA methylation in precancerous cells may prevent the
development of new primary cancers in the same organ," they write.


###
Contacts:
Article: Laura Sussman, Communications Office, M. D. Anderson Cancer
Center, 713-745-2457, lsussman@...
Editorial: Edward Giovannucci, Harvard School of Public Health,
egiovann@...
Citations:

Article: Shen L, Kondo Y, Rosner GL, Xiao L, Hernandez NS, Vilaythong
J, et al. MGMT Promoter Methylation and Field Defect in Sporadic
Colorectal Cancer. J Natl Cancer Inst 2005;97:1330–8.
Citation: Giovannucci E, Ogino S. DNA Methylation, Field Effects, and
Colorectal Cancer. J Natl Cancer Inst 2005;97:1317–9.
Note: The Journal of the National Cancer Institute is published by
Oxford University Press and is not affiliated with the National
Cancer Institute. Attribution to the Journal of the National Cancer
Institute is requested in all news coverage. Visit the Journal online
at http://jncicancerspectrum.oxfordjournals.org/.