Genes Predict Pancreatic Cancer Risk, Outcome
CancerWise - April 2009
Abnormalities in genes that repair mistakes in DNA reproduction one day may help identify who is at risk of developing pancreatic cancer and how people will fare if they get this aggressive cancer.
Researchers at M. D. Anderson released two studies on the role of single nucleotide polymorphisms (SNPs, pronounced “snips”) in pancreatic cancer.
"We consider DNA repair to be the guardian of the genome," says Donghui Li, Ph.D., professor in the Department of Gastrointestinal Medical Oncology at M. D. Anderson. "If something is wrong with the guard, the genes are more readily attacked by damaging agents."
Defective SNPs can act alone or with risk factors to increase the threat of pancreatic cancer.
Risk factors for pancreatic cancer are:
- Family history of cancer
- Cigarette smoking
- Heavy alcohol consumption
Li and her colleagues set out to identify DNA repair genes that could help predict pancreatic cancer risk. The group’s research was published in the Jan. 15 issue of Clinical Cancer Research.
Significance of study
"We know that people with diabetes have a higher risk of developing pancreatic cancer, but we don't know who actually will develop the disease and who will not," lead author Li says. "The same is true for smokers. But we can't do CT(computed tomography) scans on every diabetic or every smoker.
"We need to develop biomarkers that will enable us to do a quick genetic test on patients who are diabetic or heavy smokers, or have a family history of pancreatic cancer," she says. "We could then screen those with the highest risk and monitor them more closely."
The study included:
- 734 patients with pancreatic cancer
- 780 healthy people
Researchers examined nine variants of seven SNPs: LIG3, LIG4, OGG1, ATM, POLB, RAD54L and RECQL.
They looked for:
- Direct effects of SNPs on pancreatic cancer risk
- SNP and pancreatic cancer risk factor interaction
The risk of developing pancreatic cancer was 77% lower among people with the variant form of the LIG3 gene. In contrast, people who carried the variant form of the ATM gene were more than twice as likely to develop the disease.
Investigators found no significant correlation between the SNPs and smoking, heavy alcohol consumption or excess body weight.
However, two of the gene variants (ATM D1853N and LIG4 C54T) interacted with diabetes to increase pancreatic cancer risk.
Understanding the role of DNA repair genes in pancreatic cancer also would help researchers gain insight about the disease, which may offer an opportunity to develop preventive strategies.
SNPs that help repair DNA mismatches may predict survival of patients with pancreatic cancer and help physicians choose the optimum treatment for each patient.
This study was presented by Li at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January and published in the Feb. 23 issue of Journal of Clinical Oncology.
It looked at the association between SNPs and:
- Response to Gemzar® (gemcitabine)
- Likelihood of removing the entire tumor
- Patient survival
Significance of study
"Gemcitabine is a major chemotherapeutic agent used to treat pancreatic cancer, but we don't understand why some patients respond but most patients do not," Li says.
Li's group obtained DNA samples from 154 patients whose pancreatic tumors had the potential to be surgically removed. They were participating in Phase II clinical trials of preoperative gemcitabine-based chemoradiation. Researchers followed these patients for a median time of 50 months.
The researchers evaluated 15 SNPs among eight mismatch-repair genes: EXO1, MLH1, MSH2, MSH3, MSH6, PMS1, TREX1 and TP73.
Researchers found associations between:
- Five genotypes and response to gemcitabine
- Six genotypes and tumor resectability
- 10 genotypes and survival
The combined effects of SNPs on patient survival were dramatic. Twenty of 25 patients with zero or one abnormal genotype were alive at the completion of the study.
In contrast, median survival times were:
- 36 months for patients with two adverse SNPs
- 24 months for those with three
- 16 months for those with four
- 13 months for those with five
- Eight months for those with six or seven
If confirmed by other researchers, these findings could have a profound effect on how pancreatic cancer is treated.
"We hope that in the future we will be able to run a genetic test that will help doctors predict an outcome and select the best therapy for each patient," Li says.
— Adapted by Dawn Dorsey from an M. D. Anderson news release
M. D. Anderson resources:
- All About Pancreatic Cancer (American Cancer Society)
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