Genetic Quirk Unexpectedly Impacts Colon Tumor Formation

Unexpected results from an ongoing experiment in the lab of Kristi Neufeld, PhD, co-leader of the Cancer Biology Program, led to a potentially important discovery that could have an impact on how cancer researchers do studies on mice, and possibly prevent colon cancer in people.

Dr. Neufeld studies the adenomatous polyposis coli (APC) protein, which protects against colon cancer. Most of her experiments involve testing mice with APC mutations (which cause colon cancer) and seeing if any new drug compounds will work against the mutations.

While doing one of these experiments a few years ago, Dr. Neufeld’s team discovered that some mice weren’t developing colon polyps like mice with APC mutations normally do. The mice without polyps could not be used to test drugs; however, Maged Zeineldin, PhD, a postdoctoral fellow working in Dr. Neufeld’s lab, didn’t want to let the research go to waste.

They discovered why these mice weren’t developing polyps – they had a quirk in a genetic modifier called Pla2g2a that turned out to be protecting them from tumors, what she deemed a polymorphism. And because they were using nude mice, which are outbred and have varying genetic makeups, some of the mice didn’t develop as many polyps as others did.

“We’re thinking maybe that could affect tumorigenicity studies,” Dr. Neufeld said. “If you’re injecting the mice with a human colon cancer cell and you don’t know whether that polymorphism is there or not, it could potentially change the outcome of the experiment.”

Dr. Neufeld will now screen her mice for this Pla2g2a polymorphism and hopes to make other cancer researchers, especially those who test new drug therapies, aware of how genetic modifiers alter the results of an experiment.

“We think this is really important because if someone injects cancer cells, grows a tumor and then injects a compound to see if it treats the cancer, you don’t know if what you’re seeing is a result of the actual compound or if it was affected by the differences in genes in these outbred nude mice,” she explained.

One change makes all the difference

Though this work was a side project from her concentration on the APC protein, Dr. Neufeld hopes to collaborate with another lab to determine if this genetic modifier is something that would have a similar effect in humans. Would the overexpression of Pla2g2a prevent polyps from forming in a human colon? Would it be as simple as infecting the gut with bacteria that expresses the Pla2g2a polymorphism?

Though the answers to those questions are likely many years away, discoveries like this could potentially aid in preventing cancer or screening for a modifier that could impact whether someone is at risk for colon cancer. Perhaps doctors will someday screen for the absence or presence of the Pla2g2a like they do for the BRCA or HER2 genes, but first researchers would have to see if the Pla2g2a polymorphism helps to prevent polyps like it did in the mice, according to Dr. Neufeld.

“We would want to figure out if simply expressing that polymorphism would be enough in humans and if it would have the same protective properties,” Dr. Neufeld said. “We were just trying to salvage something from our original experiment, but it turned out to be a lot more interesting. I think the lesson is that if you have the time, sometimes following through on things that don’t make sense can really pay off.”

She noted this has likely happened before in numerous cancer experiments, but researchers just see these mice as outliers and remove them from the experiment altogether. Dr. Neufeld suspects other researchers also think genetic modifiers are responsible, like she did with her mice.

Dominant vs. recessive

Genetic modifiers are changes in a gene which result in the modification of another gene’s function. For example, if a person’s hair color is the A allele (one variant of a gene) and the shade of a person’s hair is controlled by the C allele, the C allele doesn’t mask the effect of the A allele, but rather just changes how it’s expressed. A person could have light brown hair or dark brown hair, depending on whether or not the dominant or recessive allele is expressed. In the case of Plag2ga, the mice either have two sensitive or resistant alleles, or one of each.

To confirm that the Pla2g2a modifier did indeed play a role in whether or not the nude mice formed colon polyps, Dr. Neufeld’s team injected mice with colon cancer cells to see if tumors would form and screened them for the Pla2g2a polymorphism.

“What we found is that the formation of tumors correlated with the presence or absence of these resistant alleles,” Dr. Neufeld said. “Mice with resistant alleles (the polymorphism) had fewer tumors than the ones with the sensitive alleles.”

This is only one change in one genetic modifier – there are hundreds of others that haven’t yet been identified that could be affecting cancer research experiments and influence prevention and treatment options in the future.

“There are so many genetic modifiers where any change to them can affect so many other things, so any gene alteration at all could potentially have an effect on cancer,” said Dr. Neufeld. “Even in the case of Pla2g2a, it’s not clear why it protects against these polyps or why it protects against tumor formation. It’s still something we have to figure out.”

Funding sources

  • RO1 CA10922, Kristi Neufeld (PI): “Nuclear Functions of the Tumor Suppressor Protein APC”
  • P20RR016475: National Center for Research Resources
  • P20 GM103418: National Institute of General Medical Sciences
  • The University of Kansas Cancer Center: Student Summer Research Training Program

Relevant publications

  • Miller, Matthew A., Maged Zeineldin, and Kristi L. Neufeld. "Demonstrating a role for nuclear Adenomatous polyposis coli in intestinal cell differentiation." Cancer Research 73.8 Supplement (2013): 1978-1978.
  • Zeineldin, Maged, and Kristi L. Neufeld. "More than two decades of Apc modeling in rodents." Biochimica et Biophysica Acta (BBA)-Reviews on Cancer1836.1 (2013): 80-89.
  • Zeineldin, Maged, and Kristi L. Neufeld. "Understanding phenotypic variation in rodent models with germline Apc mutations." Cancer research 73.8 (2013): 2389-2399.

The Origin of Cancer

Most cancers start out from an oncogene, an abnormal gene which predisposes cells to turn cancerous. Oncogenes divide uncontrollably, unlike regular cells which control the starting and stopping of cell growth.

Oncogenes can be activated by a number of things: inherited mutations, UV rays, chemicals such as those found in cigarettes or viruses like the human papillomavirus (HPV).

Researchers are working to target oncogenes for drug therapies to slow or stop the growth of cancer.