Deadly Pancreatic Cancer Develops Much More Slowly Than We Thought, Raising Hopes Of Earlier Detection

Deadly Pancreatic Cancer Develops Much More Slowly Than We Thought, Raising Hopes Of Earlier Detection
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Main Category: Pancreatic Cancer
Also Included In: Genetics; Medical Devices / Diagnostics
Article Date: 28 Oct 2010 - 2:00 PDT

Scientists who studied the genetics of pancreatic cancer, one of the deadliest cancers with fewer than five per cent of patients still alive five years after diagnosis, found that it takes much longer to grow than we thought, as long as 20 years to become lethal, but the good news is this extends the window of opportunity for earlier detection, especially if a blood or stool test could be developed to pick up some of the early cancer-causing mutations that they found.

You can read a paper on how senior author Dr Christine Iacobuzio-Donahue, a pathologist at Johns Hopkins University School of Medicine in Baltimore, Maryland in the US, and colleagues arrived at these findings in the 28 October issue of the journal Nature.

Co-leading the study was Dr Bert Vogelstein, a Howard Hughes Medical Institute investigator at the Johns Hopkins Kimmel Cancer Center. He said in a statement there are two theories for why pancreatic cancer is so deadly.

The first theory is that the tumors are very aggressive right from the start and spread rapidly to other organs. The other theory is that they are not aggressive but spread slowly, with symptoms appearing very late in the process, so that the chances of survival are much diminished.

"We were surprised and pleased to discover that this second theory is correct, at least for a major fraction of tumors," said Vogelstein.

"It means that there is a window of opportunity for early detection of pancreatic cancer," he added.

For the study, Iacobuzio-Donahue, Vogelstein and colleagues investigated autopsy tissue from seven patients who died with pancreatic cancer. The samples included tissue from primary tumors in the pancreas, and also from lesions of where it had spread (metastased) to the lungs, liver and other organs.

They sequenced the DNA of all the genes in both types of tissue and compared them to see if there were any genetic differences between primary pancreatic tumors and metastatic lesions.

Across all seven patients, they found 61 cancer-related mutations on average per metastatic lesion, and that 64 per cent of them, on average, were also present in the primary tumor.

Using a technique termed "molecular clock", and observing the steady rate of growth of cancer cells in lab cultures, they estimated how long it took for each of the mutations to grow in the primary tumors and the metastased lesions.

The results showed that on average, over 20 years elapsed between the appearance of the first mutated pancreatic cancer cell and death:
It took 11.7 years on average, for a mature primary tumor to form in the pancreas after the first cancer-related mutation appeared in a cell.

It took an average of another 6.8 years before the primary tumor sent out a metastatic lesion to another organ.

After that, it was another 2.7 years on average, before the patient died.
Vogelstein said this is similar to what we've seen before in colorectal cancers, the tumors take decades to evolve.

However, unlike other cancers, pancreatic cancer usually shows no symptoms until it has spread. The first symptom is usually jaundice, but that only appears after lesions have started growing in the liver.

Vogelstein said these findings raise the chance that a blood or stool test could be developed to look for signs of early cancer-causing mutations.

"It gives us hope that we will eventually be able to reduce morbidity and mortality from pancreatic cancer through earlier detection," he said, adding that he and his team are already working on such a test for colorectal cancer.

The researchers also made another interesting discovery about how pancreatic tumors evolve. They found that the tumors continue to accumulate genetic mutations after they first appear: when they analyzed the genes of pieces of tumor they found they were made of genetically distinct sub-tumors.

Vogelstein said they found what looked like a "series of generations of tumor clones: fathers, grandfathers, great-grandfathers, you could say," within the primary tumor.

He said this showed the primary tumor was not a single tumor but an accumulation of several genetically distinct tumors.

They were also able to locate within the primary tumor, the subclone that had given rise to each metastased lesion.

"That's fascinating from a basic science perspective and gives us some deep insights into how these tumors evolve," said Vogelstein.

"Distant metastasis occurs late during the genetic evolution of pancreatic cancer."
Shinichi Yachida, Siân Jones, Ivana Bozic, Tibor Antal, Rebecca Leary, Baojin Fu, Mihoko Kamiyama, Ralph H. Hruban, James R. Eshleman, Martin A. Nowak, Victor E. Velculescu, Kenneth W. Kinzler, Bert Vogelstein, & Christine A. Iacobuzio- Donahue.
Nature, 467, 1114-1117 (28 October 2010).
DOI:10.1038/nature09515.

Additional source: Howard Hughes Medical Institute.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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