A team of researchers led by investigators at the Ontario Institute for Cancer Research (OICR) and University Health Network's Princess Margaret Cancer Centre has published new findings that challenge current beliefs about how and why pancreatic cancer is so aggressive. The new findings recently appeared in the journal Nature, in an article entitled “A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.”
Pancreatic cancer often has an extremely rapid onset, and the disease is often inoperable by the time the patient experiences symptoms. Pancreatic cancer's tendency to appear at an advanced stage has long been a medical mystery. Yet in the new study, researchers using whole genome sequencing (WGS) were able to reconstruct the history of pancreatic cancer development in 100 independent tumors. Surprisingly, they found that many of the important alterations that are thought to cause this disease occur all at once, analogous to the "big bang" model proposed for colon cancer previously.
"When we started this project many years ago, we wanted to make better sense of how this disease progresses clinically," explained the Nature article's lead author, Faiyaz Notta, Ph.D., principal investigator at the Princess Margaret Cancer Centre and an OICR fellow. "This disease can go from being a local cancer, restricted to the pancreas, to becoming fully metastatic very rapidly. The traditional view of the biology of the disease just didn't jibe with what happens clinically. And it's hard to move forward in trying to find new treatments if you can't link the biology of the tumor to the clinical reality of the disease. Our findings show a very different path for how this disease develops and puts the clinical problem of this disease into better perspective. We can make more sense of why this disease is so aggressive and can advance so quickly."
Pancreatic cancer is a highly aggressive and deadly form of cancer. It is expected to be the second leading cause of cancer-related death by 2030. Improving clinical outcomes has proven stubbornly difficult, highlighting the urgent need for scientific advances.
“Using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumor-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order,” the authors wrote. “Two-thirds of tumors harbor complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set off invasive cancer growth.”
The new findings open up important new pathways of investigation that could lead to the ability to better diagnose pancreatic cancer, predict how it will develop, and determine how and when it will metastasize. Moreover, the new data could also be applicable to other aggressive tumor types.
"Pancreatic cancer is one of the most deadly types of cancer and still one of the least understood," noted senior study investigator Steven Gallinger, M.D., head of the Hepatobiliary/Pancreatic Surgical Oncology Program at the University Health Network and Mount Sinai Hospital. "These findings provide us with a new understanding of how pancreatic cancer develops and a path forward to identify better strategies to diagnose and target this terrible disease."