Advances in cancer diagnosis
We’re used to thinking about DNA in containers: nuclei, mitochondria, bacteria, viral particles. But there’s lots of DNA pieces flowing through our bloodstream all the time. This cell-free DNA can be captured and analyzed, just like the DNA in sewage can be tested for COVID.
“UCLA scientists have developed a simple and cost-effective blood test that, in early studies, shows promise in detecting multiple cancers, various liver conditions and organ abnormalities simultaneously by analyzing DNA fragments circulating in the bloodstream.
“The test, described in the journal Proceedings of the National Academy of Sciences, could offer a powerful and more affordable approach to early disease detection and comprehensive health monitoring.
“Early detection is crucial,” said Dr. Jasmine Zhou, the study’s senior author, a professor of pathology and laboratory medicine and investigator at the UCLA Health Jonsson Comprehensive Cancer Center. “Survival rates are far higher when cancers are caught before they spread. If you detect cancer at stage one, outcomes are dramatically better than at stage four.”
As a PhD geneticist, this is thrilling to me. While I never anticipated this diagnostic tool, I keenly appreciate its power as an apotheosis of genomics.
genomics-based disease testing
“UCLA scientists have developed a simple and cost-effective blood test that, in early studies, shows promise in detecting multiple cancers, various liver conditions and organ abnormalities simultaneously by analyzing DNA fragments circulating in the bloodstream.
“The test, described in the journal Proceedings of the National Academy of Sciences, could offer a powerful and more affordable approach to early disease detection and comprehensive health monitoring.
“Early detection is crucial,” said Dr. Jasmine Zhou, the study’s senior author, a professor of pathology and laboratory medicine and investigator at the UCLA Health Jonsson Comprehensive Cancer Center. “Survival rates are far higher when cancers are caught before they spread. If you detect cancer at stage one, outcomes are dramatically better than at stage four.”
As a PhD geneticist, this is thrilling to me. While I never anticipated this diagnostic tool, I keenly appreciate its power as an apotheosis of genomics.
genomics-based disease testing
The new method, called MethylScan, works by analyzing cell-free DNA (cfDNA), tiny fragments of genetic material released into the blood when cells die. Because cells from every organ shed DNA into the bloodstream, cfDNA carries molecular signals that reflect what is happening throughout the body.
“Every day, 50 to 70 billion cells in our body die. They don’t just disappear, their DNA goes into the bloodstream,” Zhou said. “That means we already have information from all our organs circulating in the blood.”
Joel:
I was curious as to what they called this new process . . .
@Bill,
The surprise for me is that the technique analyzes DNA methylation patterns, not just DNA sequence. The link doesn’t spell out how this works to (a) detect pathological methylations and (b) tie the pathological changes back to a source tissue or organ. I’d have to read the paper, and probably several others on which it is based. I just don’t have the appetite for that since I’m neither going to use the technique nor teach it.
Joel:
Since you will not read it . . . I had you down for an “A” for the course with the hope you might explain this further. Now it is a “C.” 🙂
I too, find some additional investigation may not be worth the extra work. You are the expert here and I am an amateur on topics such as these. Thank you for the response.
PS: quickly turning screens getting explanation to what you just wrote.
@Bill,
Well, the time it would take to winkle out all the details would require me to take a couple weeks off from AB. I don’t think you’d want that.
Actually, a younger me would be curious to figure it out, but a younger me would have kept up better in the field. Now, I just sit back and shake my head in admiration.
Joel:
I did not expect such. Just kidding you. I understand completely. There are thinks I would like to write and they are so long in doing, I sigh and pass it by.
The goal is to find tumor associated DNA set up for expression in a blood sample. They know the sequence(s) they want to look for, and they know that they get marked with methyl groups (CH3-X) if they’re being expressed. The problem is that there’s a lot of DNA in the blood, most of it from white blood cells, so they need to amplify the signal so they can ignore the noise.
The big trick seems to be whole genome bisulfite sequencing which “convert[s] unmethylated cytosines to uracil”. The idea is that CG sequences are where methylation happens. It’s at those CGs that the DNA strand can be marked for epigenetic expression or suppression by adding a methyl group. Changing the unmethylated cytosines, the Cs, into Us means that any remaining Cs were methylated. Us don’t appear normally in DNA. DNA uses Ts. RNA uses Us.
They are interested in sequences that contain CCGG or GCGC, at least four CG sites that could be methylated, and a good number of those CG sites actually methylated. So, it’s dump in one enzyme then another to select the interesting stuff. Then they use PCR (with yet another enzyme) to make copies of the stuff that has been selected as interesting because it has been methylated and so is likely to being expressed. Finally, they look for DNA sequences associated with tumors activity. Healthy people shouldn’t have any. People with tumors do, but at very low levels hence all this selection, transformation and amplification. I’m guessing the last step works a lot like a COVID or pregnancy test at least in principle. Something matches the tumor DNA and triggers some kind of marker.
At least that’s my takeaway from the paper. I’m not a biologist, but I have a science background and ramped up on this kind of stuff during COVID. I’m sure I missed a few important points, but that’s my general read.
P.S. I have no idea how people can do this for living. Consider this Q&A:
Consider this dialog:
Dereklowe: … That one, the engagingly named mitogen-activated protein kinase kinase kinase kinase 4 (not kidding) is also mentioned in the AstraZeneca paper linked above as the most common target also hit by TNIK chemical matter, …
Q: So Derek, tell me. When you have four kinases in a name, does it mean “an enzyme that phosphorylates another enzyme that phosphorylates another enzyme that phosphorylates another enzyme” sort of in a Rube Goldberg sort of way?
Dereklowe: That is *exactly* what it means!
@Kaleberg,
Nature isn’t so much an inventor as a tinkerer. Protein phosphorylation proved to be a more efficient regulatory mechanism than making and regulating multiple paralogs. It’s a small step from that to regulating the regulators, and so on up the hierarchy.
The fox knows many things; the hedgehog knows one big thing. Nature is a hedgehog.
@Kaleberg,
Thanks. I’d mostly figured that part out, except that most CpG methylation in humans is associated with gene silencing, not gene expression. The part I still don’t understand is how they tie the specific methylations and mutations to a specific tissue or organ, since all genes are present in all cells (except for rearranged Ig and T-cell receptor genes in B and T cells, respectively).