Johns Hopkins Medicine
October 23, 2013
Reporting on a small preliminary study, Johns Hopkins researchers say a simple blood test based on detection of tiny epigenetic alterations may reveal the earliest signs of pancreatic cancer, a disease that is nearly always fatal because it isn’t usually discovered until it has spread to other parts of the body.
The findings of their research, if confirmed, they say, could be an important step in reducing mortality from the cancer, which has an overall five-year survival rate of less than 5 percent and has seen few improvements in survival over the last three decades.
“We have mammograms to screen for breast cancer and colonoscopies for colon cancer but we have had nothing to help us screen for pancreatic cancer,” says Nita Ahuja, M.D., an associate professor of surgery, oncology and urology at the Johns Hopkins University School of Medicine and leader of the study described online this month in the journal Clinical Cancer Research. “While far from perfect, we think we have found an early detection marker for pancreatic cancer that may allow us to locate and attack the disease at a much earlier stage than we usually do.”
For their study, Ahuja and her colleagues were able to identify two genes, BNC1 and ADAMTS1, which together were detectable in 81 percent of blood samples from 42 people with early-stage pancreatic cancer, but not in patients without the disease or in patients with a history of pancreatitis, a risk factor for pancreatic cancer. By contrast, the commonly used PSA antigen test for prostate cancer only picks up about 20 percent of prostate cancers.
Ahuja and her colleagues found that in pancreatic cancer cells, it appears that chemical alterations to BNC1 and ADAMTS1 — epigenetic modifications that alter the way the genes function without changing the underlying DNA sequence — silence the genes and prevent them from making their protein product, the role of which is not well-understood. These alterations are caused by the addition of a methyl group to the DNA.
Using a very sensitive method called Methylation on Beads (MOB) developed by Jeff Tza-Huei Wang, Ph.D., a professor at the Whiting School of Engineering at Johns Hopkins, the researchers were able to single out, in the blood, even the smallest strands of DNA of those two genes with their added methyl groups. The technique uses nanoparticle magnets to latch on to the few molecules being shed by the tumors, which are enough to signal the presence of pancreatic cancer in the body, the researchers found.
Specifically, researchers say, they found BNC1 and ADAMTS1 in 97 percent of tissues from early-stage invasive pancreatic cancers. Surgery is the best chance for survival in pancreatic cancer, because radiation and chemotherapy are not very effective against it. The smaller the cancer — the earlier it is detected — the more likely surgery will be successful and the patient will survive.
Ahuja says the practical value of any blood test for cancer markers depends critically on its sensitivity, meaning the proportion of tumors it detects, and its specificity, meaning how many of the positive results are false alarms. The specificity of this new pair of markers is 85 percent, meaning 15 percent would be false alarms. Ahuja says she hopes further research will help refine the test, possibly by adding another gene or two, in order to go over 90 percent in both sensitivity and specificity.
Ahuja also cautions that her team still needs to duplicate the results in a larger sample of tumors, but is encouraged by the results so far. She says she doesn’t envision the blood test as a means of screening the general population, the way mammograms and colonoscopies are used to find early breast and colon cancers. Instead, she imagines it would be best used in people at high risk for developing the disease, such as those with a family history of pancreatic cancer, a previous case of pancreatitis, long-term smokers or people with the BRCA gene mutations, which are linked to breast, ovarian and pancreatic cancers.
“You have to optimize your medical resources,” says Ahuja, who hopes a commercial blood test might one day only cost $50.
She also notes that once BNC1 and ADAMTS1 are identified in a patient’s blood, further tests will be needed to locate an actual cancer.
People who test positive will likely undergo CT scanning and/or endoscopic ultrasound tests ¬— whereby a tube is placed down the throat into the stomach to image the pancreas — to search for the cancer. Surgery to remove it would presumably have a better chance of curing the disease owing to its small size and early stage.
The research is supported by grants from the National Institutes of Health’s National Cancer Institute (K23CA127141, U54CA151838, RO1CA155305, P30CA006973, T32CA126607 and CA058184) and National Institute of Environmental Health Sciences (R01 ES011858), the American College of Surgeons/Society of University Surgeons Career Development Award, the Lustgarten Foundation, the Miriam & Sheldon G. Adelson Medical Research Foundation and the National R&D program through the Dongnam Institute of Radiological & Medical Sciences funded by the Korean Ministry of Education, Science and Technology.
Other Johns Hopkins researchers involved in the study include Joo Mi Yi, Ph.D.; Angela A. Guzzetta, M.D.; Vasudev J. Bailey, Ph.D.; Stephanie R. Downing, M.D.; Katherine B. Chiappinelli, Ph.D.; Brian P. Keeley; Alejandro Stark, M.S.E.; Alexander Herrera, M.S.; Chistopher Wolfgang, M.D., Ph.D.; Emmanouil P. Pappou, M.D., Ph.D.; Christine A. Iacobuzio-Donahue, M.D., Ph.D.; Michael G. Goggins, M.B.B.Ch., M.D.; James G. Herman, M.D.; and Stephen B. Baylin, M.D.