Extrachromosomal DNA (ecDNA), DNA circles carrying cancer-associated genes, play a critical role in cancer development, according to new research led by Stanford Medicine. These DNA circles can be found in precancerous cells, and their presence accelerates the transformation to a cancerous state. This discovery paves the way for potential early diagnosis and intervention methods in cancer treatment.
Here's a conundrum for creationists to avoid or blame on 'The Fall' - so showing creationism is Christian fundamentalism, not science.
It's the finding by scientists at Stanford Medical Centre, that errors in DNA replication can cause small circles of extrachromosomal DNA (ecDNA) to form and that these can lead to the formation of cancers. ecDNAs have been found before and the suggestion was that they are produced by cancerous cells as the DNA replication becomes increasingly botched, but this new study shows they can arise in pre-cancerous cells and may well be the cause of the cell becoming cancerous.
The ecDNA contains genes that deliver a super-charged growth signal that can override a cell’s natural programming. They also contain genes likely to dampen the immune system’s response to a nascent cancer.
Creationists, of course, insist that the process of DNA replication was designed by their putative intelligent [sic] omniscient designer. An intelligent, omniscient designer will know in advance exactly what it's design will do, so this raises several questions:
- If this was the work of an intelligent designer, why should it not be regarded as malevolent and responsible for designing a process that deliberately causes cancers and so increases the suffering in the world?
- If this was not the intended outcome, why should the designer not be regarded an incompetent?
- If it was incompetent, why didn't it change its design once it realised what the outcome was? Is it either ignorant of what its design does, or doesn't it care?
Anyway, those are problems for advocates of the childish notion of design by a magic, supernatural magician, believed by those who want easy answers and the pretense of superior knowledge to that of scientists, while avoiding the bother of learning.
The problem for science is how to use this knowledge to reduce the pain and suffering in the world, because medical science, unlike creationism's supposed god is actually moral and seeks to reduce the pain and suffering in the world, and so fights a continuous battle with whatever force is tending to increase it - in this case, as any intelligent person can understand, the force is that of evolutionary arms races and the self-interest of mindless genes.
So, how did the Stanford Medical School scientists make this discovery? The Stanford Medical news release by Krista Conger, explains:
Tiny circles of DNA that defy the accepted laws of genetics are key drivers of cancer formation, according to an international study led by researchers at Stanford Medicine.
The circles, known as extrachromosomal DNA or ecDNA, often harbor cancer-associated genes called oncogenes. Because they can exist in large numbers in a cell, they deliver a super-charged growth signal that can override a cell’s natural programming. They also contain genes likely to dampen the immune system’s response to a nascent cancer, the researchers found.
Previous research had suggested that the circles, which are widespread in human cancers but rarely found in healthy cells, primarily arise in advanced tumors as the abnormal cells increasingly botch the intricate steps required to copy their DNA before each cell division. But the new study shows that the roly-poly circles can be found even in precancerous cells — and their presence jump-starts a cancerous transformation. Blocking their formation, or their effect on the cells that carry them, might stop cancers from developing, the researchers believe.
This study has profound implications for our understanding of ecDNA in tumor development. It shows the power and diversity of ecDNA as a fundamental process in cancer. It has implications for early diagnosis of precancers that put patients at risk, and it highlights the potential for earlier intervention as treatments are developed.
Professor Paul S. Mischel, MD, co-senior author
Department of Pathology
Stanford University School of Medicine, Stanford, CA, USA.
Mischel is one of six senior authors of the research, which was published April 12 in Nature. Howard Chang, MD, PhD, professor of genetics and the Virginia and D.K. Ludwig Professor in Cancer Research, is also a senior author. Other senior authors include senior staff scientist Thomas Paulson, PhD, from Seattle’s Fred Hutchison Cancer Center; assistant professor of pediatrics Sihan Wu, PhD, assistant professor at Children’s Medical Center Research Institute at the University of Texas Southwestern Medical Center; professor of computer science and engineering Vineet Bafna, PhD, from UC San Diego; and professor of cancer prevention and director of the Early Cancer Institute Rebecca Fitzgerald, MD, from the University of Cambridge.
A grand challengePeople with ecDNA in their precancerous cells are 20 to 30 times more likely than others to develop cancer. This is a huge increase, and it means we really need to pay attention to this. Because we also found that some ecDNAs carry genes that affect the immune system, it suggests that they may also promote early immune escape.
Professor Howard Y. Chang, co-senior author
Center for Personal Dynamic Regulomes
Stanford University, Stanford, CA, USA
Deciphering ecDNA’s role in cancer was one of four Cancer Grand Challenges awarded by the National Cancer Institute and Cancer Research UK in 2022. The grand challenges program was launched to bring together researchers from around the world to tackle complex research topics too daunting for any one group. Mischel was awarded $25 million to lead a team of international researchers to learn more about the circles. But first they had to jettison some key genetic principles that have guided the field for nearly 200 years.
But these assumptions hinge on the idea that all of a tumor’s DNA is neatly contained on chromosomes, which are evenly divided among daughter cells each time a cancer cell divides — ensuring that each new cell gets one, and only one, copy of each chromosome.When we think about how a tumor evolves in a patient and in response to treatment, we think of the branching trees of life proposed by Charles Darwin. This idea is so powerful that researchers often sequence the DNA from multiple parts of a tumor and draw these trees to learn about its evolution. If a mutation is there at the trunk of the tree and in all of its branches, we assume it is a key driver event in the formation of the tumor; if it is in only some branches, we assume it happened later in tumor development and may not be a good target for drug development.
Professor Paul S. Mischel, MD.
In contrast, the tiny ecDNA circles swirl in a dividing cell like bubbles circling a bathtub drain and are portioned willy-nilly between the new daughter cells. One may get nearly all the circles; the other, almost none. As the generations accumulate, the evolutionary tree favored by Darwin begins to look decidedly odd, with the appearance of ecDNA-bearing cells sprinkled among the branches like haphazardly hung Christmas lights.
Pinpointing a reasonSome researchers have looked at the evolutionary trees and decided that, because you see it here, but not there, it must be that ecDNA formation is a late event and probably isn’t important when considering treatments. Our team thought that interpretation was wrong.
Professor Paul S. Mischel, MD.
To get to the bottom of the tiny circles, Mischel, Chang and their collaborators turned to a specific example of cancer development — people with a condition known as Barrett’s esophagus, which occurs when the cells lining the lower part of the esophagus are damaged by acid reflux and become more like cells lining the intestine than healthy esophageal tissue. About 1% of these people develop esophageal cancer, which is difficult to treat and has a high mortality rate. Because the outcome is so poor, people with Barrett’s esophagus are routinely monitored with endoscopies and biopsies of the abnormal tissue. Because of these frequent biopsies, the researchers had access to tissue samples collected both before and after cancers developed.
The researchers assessed the prevalence of ecDNA, and identified the genes they carried, in biopsies from nearly 300 people with Barrett’s esophagus or esophageal cancer treated at the University of Cambridge or at Seattle’s Fred Hutchison Cancer Center, where individual patients were studied as the cancer developed. They found that the prevalence of ecDNA increased from 24% to 43% in early- versus late-stage esophageal cancer, indicating the continual formation of the DNA circles during cancer progression. More tellingly, they found that 33% of people with Barrett’s esophagus who developed esophageal cancer had ecDNA in their precancerous cells. In contrast, only one out of 40 people who didn’t develop cancer had cells with ecDNA, and that individual passed away due to another cause.
The conclusions were remarkable. We see that ecDNA can arise in these precancerous cells, and that if it is there, the patient is going to get cancer. We also saw the continuous formation of ecDNA as the cancer progresses, indicating that it is advantageous to cancer growth. Finally, we saw that the ecDNA can contain immune-modulatory genes in addition to oncogenes.
Professor Paul S. Mischel, MD.
If a gene is carried on ecDNA, it is very likely to be important for cancer. These circles are not only giving us new targets for cancer diagnosis and drug development; they are also teaching us what is important for tumor growth.
Professor Howard Y. Chang
What to look at next
The researchers are planning to explore more about how ecDNAs arise in cancer cells and how they work together to make proteins that drive cancer cell growth. They saw that cancers with ecDNA were likely to also have mutations in a protein called p53. Sometimes called “the guardian of the genome,” p53 temporarily halts the cell cycle to allow cells to repair damage or mutations to their DNA before beginning to divide.
We want to learn more about the landscape of ecDNA in precancers and the risks it confers. We also want to know if we can stop its formation or activity; how to improve our ability to detect their presence; how they affect the immune system; and whether there are opportunities for new, novel therapies. There is much more to learn, and our team is excited to tackle all these issues. But what we do know for certain is that these tiny DNA circles are a very big deal in cancer.
Professor Paul S. Mischel, MD.
The team’s findings were published open access last April in the journal Nature:
AbstractIn evolutionary biology terms, the fact that DNA replication sometimes goes wrong and produces cancers, especially when those cancers tend to occur in later life when the victim has already produced offspring, makes perfect sense as the sub-optimal result of an unnecessarily complex but utilitarian method of cell replication. It makes no sense at all as the intentional outcome of the design of an omnipotent, all-loving designer.
Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer1,2,3,4,5,6. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett’s oesophagus. These data included 206 biopsies in Barrett’s oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case–control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett’s-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection.
Luebeck, J., Ng, A.W.T., Galipeau, P.C. et al.
Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus. Nature 616, 798–805 (2023). https://doi.org/10.1038/s41586-023-05937-5
Copyright: © 2023 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)
No doubt creationists will blame The Fall, but the problem is not only that it gives the game away and reveals that creationism is religion, not science and needs to invoke unevidenced, supernatural entities and superstitions. It is also tantamount to claiming that there is some other creative force or entity capable of interfering with their putative, omnipotent creator god, against which this god is powerless, or ignorant and/or indifferent to the pain and suffering it causes. This is far from the omnipotent, omniscient, all-loving god they purport to be worshiping.
In their rush to win new recruits for the cult, creationists seem to be prepared to trample their god's reputation in the mud - which makes you wonder just what their real motive is. It certainly isn't promoting an all-loving, omnipotent god; it looks more like promoting the self-interests of the self-aggrandizing cult leaders.
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