Predict Pancreatic Cancer Risk with DNA Repair Genes

An issue about pancreatic cancer has been released by Research Team from Univ. of Texas (Jan 15, 2009). The issue is abnormalities in genes that repair mistakes in DNA replication may help identify people who are high risk of developing pancreatic cancer.

Defects in this critical DNA repair genes can occur alone or in combination with traditional risk factors known to be an individual probability diagnosed with this very aggressive form of cancer.

"We consider DNA repair to be the guardian of the genome,"Donghui Li, Ph.D. said, profesor in the Dept of Gastrointestinal Medical Oncology at M. D. Anderson. "If something is wrong with the guard, the genes are more readily attacked by tobacco carcinogens and other damaging agents."

With this in mind, Li and her colleagues set out to identify DNA repair genes that may act as sensitive markers to predict pancreatic cancer risk. In a case-control study of 734 patients with pancreatic cancer and 780 healthy subjects, they examined nine variants of seven DNA repair genes. The repair genes study were: LIG3, LIG4, OGG1, ATM, POLB, RAD54L and RECQL.

The researchers looked for direct effects of genetic variations (also known as single nucleotide polymorphisms) in pancreatic cancer risk and possible interactions between genetic variants and known risk factors for the disease, including family history of cancer, diabetes, heavy smoking, heavy alcohol use and overweight. They also found that the risk of developing pancreatic cancer was 77 percent lower among individuals with the variant form of the LIG3 gene (LIG3 G-39A AA). In contrast, people who carried the variant form of the ATM gene (ATM D1853N AA) were more than twice as likely to develop the disease as those without the genetic variation.

When the researchers examined the possibility of interactions genetic variants known risk factors, they found that there is no significant interaction between the abnormal DNA repair genes and smoking, heavy alcohol or excess body weight. However, two of the genetic variants (ATM D1853N and LIG4 C54T) has an interaction with diabetes to affect pancreatic cancer risk.

The ultimate goal of this research is to identify high-risk individuals for closer monitoring and follow up, Li said. "We know that people with diabetes have a higher risk of developing pancreatic cancer, but we don't know who will actually develop the disease and who will not," Li said. "The same is true for smokers. But we can't do CT scans on every diabetic or every smoker.

"We need to develop biomarkers that will enable us to do a quick genetic test on a diabetic patient, heavy smoker or someone with a family history of pancreatic cancer," she continued. "We could then do a screening test, identify those with the highest risk, and monitor them more closely."

Understanding the role of the variant DNA repair genes in the development and prognosis of pancreatic cancer would also give researchers more understanding of their functional significance. This increased knowledge should promote the development of new therapeutic strategies for these abnormal genes.

The research was funded by grants from the National Cancer Institute, National Institute of Environmental Health Sciences Center, and the Lockton pancreatic cancer research funds.