Pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order – A Study of changes in DNA copy number and their associated rearrangements in tumour-enriched genomes: Mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory.
Reporter: Aviva Lev-Ari, PhD, RN
I thank David Orchard-Webb, PhD for bringing to my attention the following article:
The post New findings challenge current view of how pancreatic cancer develops appeared first on Biotechnology Focus.
What are the scientific implications of the results published in the original article on 10/12/2016? The conclusion is the title of this post.
New findings challenge current view of how pancreatic cancer develops
https://news.oicr.on.ca/2016/10/challenging-current-view-pancreatic-cancer/
- Using whole genome sequencing, the team reconstructed the history of pancreatic cancer development in 100 independent tumours
- important alterations that are thought to cause this disease actually occur “all at once”
- 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.”
- The 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.
- The findings could also be applicable to other aggressive tumour types. New approaches to diagnosing and treating pancreatic cancer using this information could lead to better outcomes for patients.
Ontario Institute for Cancer Research.
“New findings challenge current view of how pancreatic cancer develops.”
ScienceDaily. ScienceDaily, 12 October 2016. www.sciencedaily.com/releases/2016/10/161012140333.htm
New findings challenge current view of how pancreatic cancer develops
http://medicalxpress.com/news/2016-10-current-view-pancreatic-cancer.html
Original Article in Nature
A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
- Received
- 08 August 2016
- Accepted
- 02 September 2016
- Published online
- 12 October 2016
Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development1. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations2, 3, 4, 5 (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage2, 5, 6, 7, 8, 9, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage10. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection11, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory12. 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. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
SOURCE
http://www.nature.com/nature/journal/vaop/ncurrent/full/nature19823.html#affil-auth
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