Pancreatic cancer: Sequencing study challenges thinking on disease progression

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Pancreatic cancer is rarely detected in the early stages, as early symptoms are often vague and unrecognized. The result is that by the time diagnosis occurs, the disease is often well advanced, leaving patients with inoperable tumors and very poor prognoses. This tendency for the cancer to appear suddenly has been somewhat of a medical mystery. Now, a genome sequencing study proposes that the disease develops in a different way to that posed in current models. The findings open new avenues for improving diagnosis and predictions of disease spread.

The accepted model of pancreatic cancer is that it develops stepwise – through a sequence of genetic alterations, and it progresses gradually – because each alteration is acquired independently.

Now, in a new Nature paper, researchers from Canada challenge this model.

Through sequencing the whole genomes of 100 pancreatic cancer tumors, they mapped their history and found disease progression is “neither gradual nor follows the accepted mutation order.”

Scientific progress in pancreatic cancer has been outpaced by advances made in most other cancers.

The result is that while the survival rate for many cancers have improved dramatically in recent decades, most patients with pancreatic cancer rarely survive more than 5 years after diagnosis.

Pancreatic cancer is expected to be the second leading cause of cancer-related death by 2030. The need for scientific advances to improve clinical outcomes for patients has never been greater.

Conventional model does not line up with clinical reality

Commenting on pancreatic cancer, Dr. Faiyaz Notta, lead author of the new paper and a research fellow at the Ontario Institute for Cancer Research (OICR) in Toronto, says:

Fast facts about pancreatic cancer

  • Pancreatic cancer accounts for about 3 percent of all cancers in the United States and about 7 percent of cancer deaths
  • Estimates suggest about 53,070 Americans will be diagnosed with pancreatic cancer in 2016
  • The average lifetime risk for men and women is about 1 in 65, or 1.5 percent.

“This disease can go from being a local cancer, restricted to the pancreas, to becoming fully metastatic very rapidly.”

He explains that the conventional view of disease progression did not line up with what you see in the clinic.

This makes it “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,” he adds.

In their paper, the researchers note how the current model of pancreatic cancer suggests it develops through a particular sequence of alterations in certain genes – notably “KRAS, followed by CDKN2A, then TP53 and SMAD4.”

Also, the model assumes this path is gradual because “each alteration is acquired independently.”

While there have been some criticisms of the model, it has prevailed, and is often used as a clinical explanation for why pancreatic cancer evolves slowly and presents at a late stage.

“However,” note the authors, “the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual.”

Pancreatic cancer occurs more like ‘big bang’

For their study, Dr. Notta and colleagues used new genomic tools to track changes in DNA copy number and associated alterations in tumor-enriched genomes.

The study of copy number changes in DNA is a relatively new field in health and disease research. At first, when genes were discovered, it was thought our cells only had two copies, one from each biological parent. However, then we found that copying errors can occur during mitosis – the complex process of copying billions of chemical bases or “letters of DNA code” each time a cell divides.

Some of these errors result in missing bits of DNA, while others result in more copies. The consequences have an effect on cell function, and in some cases give rise to cancer.

Dr. Notta and colleagues found that two thirds of the tumors they examined harbored “complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium.”

They go on to note that in “a subset of cases,” the consequence of such errors is that invasive cancer growth arises from simultaneous rather than sequential genetic events.

In other words, this suggests pancreatic cancer arises more like a “big bang” rather than from a stepwise process.

The authors hope that their study will lead to new avenues of investigation that result in improved pancreatic cancer diagnoses and predictions of disease spread, and provide useful insights for other aggressive cancers.

“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 about why this disease is so aggressive and can advance so quickly.”

Dr. Faiyaz Notta

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