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colon cancer

When cells fix DNA the wrong way

Cells sometimes “fix” DNA the wrong way, creating an extra mutation, Emory scientists have revealed.

Biologist Gray Crouse, PhD, and radiation oncologist Yoke Wah Kow, PhD, recently published a paper in Proceedings of the National Academy of Sciences that shows how mismatch repair can introduce mutations in nondividing cells. Their paper was recognized by the National Institute of Environmental Health Sciences as an extramural paper of the month. The first author is lead research specialist Gina Rodriguez.

In DNA, a mismatch is when the bases on the two DNA strands do not conform to Watson-Crick rules, such as G with T or A with C. Mismatches can be introduced into DNA through copying errors as well as some kinds of DNA damage.

If the cell “fixes” the wrong side, that will introduce a mutation (see diagram). So how does the cell know which side of the mismatch needs to be repaired? Usually mismatch repair is tied to DNA replication. Replication enzymes appear to somehow mark the recently copied strand as being the one to replace — exactly how cells accomplish this is an active area of research.

In some situations, mismatch repair could introduce mutations into DNA.

Overall, mismatch repair is a good thing, from the point of view of preventing cancer. Inherited deficiencies in mismatch repair enzymes lead to an accumulation of mutations and an increased risk of colon cancer and other types of cancer.

But many of the cells in our bodies, such as muscle cells and neurons, have stopped dividing more or less permanently (in contrast with the colon). That means they no longer need to replicate their DNA. Other cells, such as resting white blood cells, have stopped dividing temporarily. Mutations in nondividing cells may have implications for aging and cancer formation in some tissues.

Through clever experimental design, Crouse’s team was able to isolate examples of when mismatch repair occurred in the absence of DNA replication.

As the NIEHS Newsletter notes:

“The researchers introduced specific mispairs into the DNA of yeast cells in a way that let them observe the very rare event of non-strand dependent DNA repair. They found that mispairs, not repaired during replication, sometimes underwent mismatch repair later when the cells were no longer dividing. This repair was not strand dependent and sometimes introduced mutations into the DNA sequence that allowed cells to resume growth. In one case, they observed such mutations arising in cells that had been in a non-dividing state for several days.”

Although the Emory team’s research was performed on yeast, the mechanisms of mismatch repair are highly conserved in mammalian cells. Their results could also shed light on a process that takes place in the immune system called somatic hypermutation, in which mutations fine-tune antibody genes to make the most potent antibodies.

Posted on by Quinn Eastman in Cancer 2 Comments

Hold out your finger: Epidemiologist developing test for colon cancer risk

Years from now physicians may be able to determine whether you’re at increased risk for colorectal cancer by drawing blood from the tip of your finger.

Emory University researchers are working to identify biomarkers to detect a person’s chances of developing colon cancer. Much like blood pressure and cholesterol tests can indicate heart disease risk, researchers here hope that some day the makeup of blood and urine will be able to tell who’s at risk for colorectal cancer, why they may be at risk and what they can do to reduce their risk.

Postdoctoral fellows Joy Owen and Veronika Fedirko examine samples in Robin Bostick’s lab at the Winship Cancer Institute of Emory University.

For now, the Emory study team is analyzing the rectal tissue samples of people with colon adenomatous polyps, non-cancerous growths considered precursors to colon cancer, and comparing them to rectal tissue samples from people who don’t have polyps. They’re also looking at whether the differences they detect in rectal tissue can also be found in blood or urine. Currently, no accepted tests exist to determine whether someone may be at risk for colon cancer.

“Most people would rather provide a blood or urine sample than get a rectal biopsy,” says Robin Bostick, MD, MPH, Rollins School of Public Health epidemiology professor and study principal investigator. Bostick is also a clinical faculty member at the Winship Cancer Institute at Emory and a Georgia Cancer Coalition Distinguished Cancer Scholar.

Read more

Posted on by adobbs in Cancer 1 Comment

Aspirin may aid colorectal cancer survival

This week’s Journal of the American Medical Association (JAMA) reports on the potential benefits of aspirin following a colorectal cancer diagnosis.

Dr. Vincent Yang

Vincent Yang, MD, PhD

Emory digestive disease expert Vincent W. Yang, MD, PhD, professor and director of the Division of Digestive Diseases, Emory School of Medicine, comments on the new study:

A large body of evidence shows that regular aspirin use can reduce the formation of colorectal cancer. Aspirin inhibits the activity of an enzyme called cyclooxygenase-2, or COX-2, that is often over-expressed in colorectal cancer.

In the Aug. 12 issue of JAMA, a study led by Andrew Chan, MD, MPH, of the Harvard Medical School, shows that regular aspirin use reduces deaths in patients who had been diagnosed with colon cancer. The study includes two large, diverse groups of individuals who were followed for more than 20 years for various health-related issues.

The individuals who developed colorectal cancer during the follow–up period and had used aspirin regularly had a lower death rate than those patients who developed colon cancers and did not take aspirin. More importantly, the benefit patients received from regularly using aspirin was more apparent if their cancers were positive for COX-2.

The results of this new study are consistent with the earlier finding reported in medical journals about aspirin’s chemopreventive effect on colorectal cancer. However, it should be noted that this study is observational by nature and that regular aspirin use can result in significant toxicities.

To learn more about the routine use of aspirin as an adjunct treatment for colorectal cancer, studies that are blinded and randomized placebo-controlled are necessary. Such clinical trials have been conducted which proved that aspirin taken at 81 mg or 325 mg per day is effective in preventing the recurrence of colorectal adenomas (polyps) after they are removed during screening colonoscopy.

A similar clinical trial could be conducted to test the ability of aspirin to prevent colorectal cancer recurrence. Perhaps patients could first be classified based on the COX-2 levels in their tumors before being randomized into the trial. A potential outcome would be that patients with COX-2-positive tumors would receive more benefit from aspirin use than those with tumors that are COX-2-negative. Chan’s JAMA findings are a catalyst for further study.

Yang is also professor of hematology and oncology at Emory Winship Cancer Institute.

Posted on by adobbs in Uncategorized Leave a comment