A ‘Big Bang’ Theory of Pancreatic Cancer Development

By Dr. Kinjal Desai

kinjal-blog-picture
Genetic changes causing pancreatic cancer occur all at once, like a big bang, due to massive genetic instability within the cell.

Relatively rare compared to more common cancers, pancreatic cancer is the fourth leading cause of cancer death in both women and men in Canada. Survival beyond 5 years is below 10%. What makes pancreatic cancer so deadly? In part, this is due to the appearance of disease symptoms when the cancer is already at a very advanced stage, despite many efforts toward an early detection. New research out of Toronto now explains why pancreatic cancer is so hard to detect early by providing insight into how it actually develops.

This recent study demonstrates that pancreatic cancer appears to develop spontaneously and rapidly following an event that causes the genome to become highly unstable, leading to thousands of genetic changes happening all at once. This is in stark contrast to the previous views on how cancer forms.

The previous theory is that cancer follows the principles of evolution much like what was identified by the great naturalist Charles Darwin. He proposed a theory of natural selection, that can be described in the following example: a bird has randomly acquired a DNA mutation that causes it to have a very long beak compared to other birds in its flock. Supposing there is a drought in the region and the only seeds available were buried deep in the ground, the once abnormal long-beaked bird now has the most advantage and survives, whereas the shorter-beaked birds in its flock are more vulnerable to starvation. When the long-beaked bird reproduces, it passes on its mutation and the long beak becomes more common or “selected” in the population. However, once the drought passes and long beaks are no longer beneficial to birds for survival, the mutation, offering no particular advantage, may start to once again become a minority in the population.

Darwin’s evolutionary model is frequently seen in cancers too. Cancer cells, which arise from normal cells, randomly acquire mutations in key genes that offer them a growth advantage. Every time a cell acquires a “cancerous” mutation, it gains greater power to grow faster and survive. These mutations, occurring randomly and in a stepwise fashion, eventually create a full-blown cancer.

But this new study from Toronto makes us rethink this theory when it comes to pancreatic cancer. It had previously been observed that pancreatic cancer becomes aggressive almost as soon as it begins forming. This new research suggests that the reason for this is that the disease-causing mutations may be occurring simultaneously with a “big bang” event, rather than in a gradual and stepwise fashion. The authors, led by a team based at the Ontario Institute of Cancer Research (OICR), used a computational method to track the genetic changes in over 100 pancreatic tumour samples to reach their conclusion.

They proposed that pancreatic cancer follows a model of evolution known as “punctuated equilibrium.” The theory was first proposed by Stephen Jay Gould and a colleague, Niles Eldredge, to refer to significant evolutionary changes that occur rapidly in spurts, and which are preceded and followed by long periods of slow and gradual changes described by Darwin’s natural selection. A similar process was also reported in colon cancer, and was referred to as a “big bang” model of cancer growth. This striking analogy is a powerful description of the rapidly changing state from normal to cancerous in certain cases.

This study offers an important new perspective to understanding cancer evolution. By more carefully identifying the different ways in which cancer can evolve in our bodies, researchers and clinicians can better design specific therapies to target them.

This article was written by Dr. Kinjal Desai. She is a postdoctoral research fellow at the Hospital for Sick Children in Toronto, where she works on medulloblastoma, the most commonly occurring malignant brain tumour in children. To learn more about Kinjal and her research check out our members page.

References:

Notta F., Chan-Seng-Yue M., Lemire M., Li Y., Wilson G.W., Connor A.A., Denroche R.E., Liang S-B., Brown A.M.K., Kim J.C., et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 538, 378–382 (20 October 2016) | doi:10.1038/nature19823

Sottoriva A., Kang H., Ma Z., Graham T.A., Salomon M.P., Zhao J., Marjoram P., Siegmund K., Press M.F., Shibata D. & Curtis C. A Big Bang model of human colorectal tumor growth. Nature Genetics 47, 209–216 (2015) | doi:10.1038/ng.3214

Darwin, C. On the Origin of Species by Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life. Nature (1859). London: John Murray, 5 (121): 502.

Eldredge, N., Gould, S.J. Punctuated equilibria: an alternative to phyletic gradualism. Models in Paleobiology (1972) pp 82-115.

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s