"Using rates of mutation as a clock, some of them appear to go back even to before birth - the key JAK2V617F mutation, long associated with these malignancies, is estimated to have shown up anywhere from the 33rd week of gestation up to the age of 11. The DNMT3 mutation, similarly, seems to have appeared from the 8th week of gestation (!) out to about the age of 8."
One of the frustrating things about cancers is that nobody knows the cancer's growth rate, how long from stage 1 to stage 2 etc, when in reality they are just categories, aka "if you have cancerous cells from your liver in your neck, then its stage 4". The problem with this is that no interval of preventative testing can be rationalized. You don't know if once a decade, or once a year, or using your privilege to get tests every 3 months would yield any help in early detection at all! The medical professionals don't know either. "Cancer" is obviously too broad, but even if you have a history of a particular type of cancer in your lineage, you're still at the same issue. We don't know if one cell flips to cancerous and defeats your body's defenses for reproduction all the way to stage 4 within 2 weeks, or whether it is over years.
Knowing that the contributing mutation can be 30-50 years prior is really helpful, and can help doctors authorize the use of their medical facilities more pointedly, while researchers continue to isolate and make peer-reviewable preventative measures that the holistic naturopaths can never do (because they don't do peer review, there may and has been accidentally salvagable parts of their form of medicine).
I'm not a cancer biologist but I work in the field of supporting cancer research and targeted therapy. My naive take is: the type of mutation and its effect on cancer progression is still being studied heavily. A lot of the understanding of biological pathways and functional impacts of these mutations are being updated and very conservatively corrected. From a systems biology point of view, the whole body is so mechanistically complex in its response to environmental and internal stress that it's a bit difficult to predict outcome / prognosis. Important cancer pathways are well studied and are usually involved in disease progression but it is still very tissue type / biomarker categorisation specific. The real driver mutations are being discovered for each cancer type but the ultimate goal is be able to see the big picture.
> The problem with this is that no interval of preventative testing can be rationalized. You don't know if once a decade, or once a year, or using your privilege to get tests every 3 months would yield any help in early detection at all!
Actually, you can study these things and see what it does to outcomes, and professionals have.
There's benefits from more frequent screening (and harms, too!). The benefits are tempered by a cancer manifesting at stage 4 could mean:
* You got unlucky with the screening interval and it showed up inbetween, or
* You have a really aggressive cancer that went from stage 1 to stage 4 in a small fraction of the screening interval.
The latter is interesting: if you are screening at an interval, the later stage cancers you find are, on average, more aggressive and faster growing. In turn, spotting them earlier doesn't necessarily lead to better outcomes.
That is: part of the reason why "finding cancer earlier" is associated with better outcomes is that it's easier to find less aggressive cancers earlier.
That’s an interesting take supporting more screening. Just having more data points for yourself and the collective conscious as well as increasing your luck.
I think that finding a cancerous liver cell in your neck means metastasis is happening, and the slow process is assumed to be complete. Unless the immune system is attacking these cells and their numbers are controlled, this would be stage 4 (while I am not a physician, let alone an oncologist).
I think that the best weapon that the general public has against cancer is autophagy, triggered by keeping blood glucose very low at least some of the time. Metabolic changes that can awaken apoptosis might kill many of these mutation carriers.
>I think that the best weapon that the general public has against cancer is autophagy, triggered by keeping blood glucose very low at least some of the time. Metabolic changes that can awaken apoptosis might kill many of these mutation carriers.
no, thats explained at how young people die, also related to a country’s food and water supply
Africa’s average age is half of North America’s, and after controlling for infant mortality still so few other people make it to the much higher life expectancy limit (which is still 10-15 years lower than North America) there that there isnt opportunity for cancer diagnosis to rear up as often! Let alone be tested for cancer to understand if that was an ailment or contributing comorbidity.
which parts? you really want me to provide sources on average age as well as life expectancy? you don't know the accepted consensuses on why societies in the continent of Africa operate in abysmal conditions to support human life uninterrupted?
I don't think I'm compelled to provide that but I'm open to counter theories
The counter theory is the comment that OP made. Your response opens with a denial of OPs theory; this response would be more effective with citations. Your theory makes sense, but I just don't see why it has to be mutually exclusive. Maybe they're both factors to varying degrees?
sure, I can accept a multipronged explanation, I already acknowledged that both of our observations are related to the food supply issues chronic on that continent, I don't think their specific correlation has been studied though so there's nothing to really say. My hypothesis is that my observations (which have been studied and are actively being addressed by many organizations) are going to have a greater weight by mere deduction: there is nothing unique enough about people in Africa that would make cancer appear earlier, and since they die earlier there and have worse preventative treatment to know other upcoming ailments, the cancer wouldn't come up because they're already dead from other basic infrastructure issues.
What I'm reading is "hey here is this ailment people get in their 60s, here's this continent where people barely survive until their 60s, do you have a citation for why people there don't frequently get that ailment there? we should really study that"
"I think that the best weapon that the general public has against cancer is autophagy"
It would be but it's so, so, ever so hard, to go without even one single meal.
I've stopped evangelizing "fasting" or even shorter intake windows.
If you can't be bothered to skip breakfast for a few weeks just to see how your body responds then let's stop wasting our time and just talk about football or something.
True, but I'd posit that the irritation and anger are effectively withdrawal symptoms; eating to avoid those symptoms is similar to keep lighting cigarettes because your hands tremble when you go without.
(Of course, it's not that black&white, and not eating at all will quickly deteriorate your health -- I'm just saying that hangriness is not the same as hunger, and learning to differentiate between the two is important)
It's not really a wish anymore. There are studies showing this, but I'm too busy to find them for you. Rhonda Patrick at https://www.foundmyfitness.com/ has interviews with various researchers on this topic. Here are some, but this is by no means exhaustive:
My two sisters and I all have diagnosed Polycythemia Vera with the JAK2 mutation present. Neither parent have the mutation or the disease. From what I understand PV is not supposed to be hereditary and clusters like ours are very rare. In retrospect the earliest signs (at the time slightly elevated platelets) were present for me when I had a very bad bout of Epstein-Barr in my early 20s and was getting regular blood counts done for months, although the first diagnosis wasn't picked up until my eldest sister was in her early 40s and the disease was non-trivially advanced.
Not too surprising in theory. During development, the body requires very fast growth. Very fast growth increases the chance of mutations.
If the selective pressure to develop quickly diminishes, then I would expect that uncontrolled growth (cancer) would be less likely as well. It would be interesting to see if this is observable in other animals (those with the shortest development times, which require the fastest bursts of growth, should be at higher risk for cancer or should have evolved solutions like extra telomerases).
This is insane. Both my mother and grandmother died because of myelofibrosis. My mother was suffering with related diseases for almost 15 years before they diagnosed the symptoms as myelofibrosis and after that doctors where still debating if the disease was there since the beginning or not
I’m not sure why it’s a surprise since a good part of cancer is not external factors but just DNA replication alone - there are many correction mechanisms, but they aren’t foolproof.
I remember reading the chapter on cancer from the Alberts "Molecular Biology of the Cell" and even though I understood the basics of cancer at that point I was still suprised by many aspects. I didn't expect just how messed up the genome of cancer cells could be, with chromosomes fusing or duplicating. Of course these kind of extreme changes are very often lethal to the cell, but in the cases where they aren't they also provide the base for breaking enough control mechanisms that would otherwise prevent cancer.
Most cancer cells are genetically unstable, some mechanisms that usually reduce mutation rates are broken in them. And this enables them to accumulate the mass of mutations they need to actually become cancer.
The most striking hypothesis I read in that chapter was that telomere shortening could actually help a cell to become cancerous. I've no idea whether that idea help up, but it was pretty much the opposite of what I expected. The basic idea is that for cells that have a way to evade the usual stop of cell division for short telomeres, this becomes an advantage. The cells still divide, shortening telomeres so much that it destabilizes the genome. If the cell can survive that, it gains a large amount of the kind of genetic instability that is needed for it to become cancerous.
A big issue is turning on things that shouldn't be turned on. A good way to imagine the chromosomes is like they are independent scripts with blocks of code. Some of the code is functional, some of it is code rot that is best left commented out. When you get a mutation that breaks the processes keeping the integrity of this codebase together, you end up sometimes seeing chunks of code cut and pasted around where it shouldn't be. Chunks fused together or separated, inverted, duplicated, removed entirely. This might result in code that should normally be commented out becoming uncommented and causing a lot of harm to the host.
This comment reminds me of the first time I saw genetic code in github and realized that the analogy of computer code to genetic code is almost not an analogy because on some level they're the same thing. I find it interesting but uncomfortable.
The thought that makes me most uncomfortable is the idea that we're reading code written by a dumb process, not a living thing. Dumb physical processes shouldn't be able to compose anything. It's like we broke into the universe's private files and found an infinity of insane scribbling, about us. It's uncanny.
A large part of the problem is that we have no idea what the proteins do, and how, where, and when they interact with one another.
It's like trying to understand Linux from just looking at the /bin directory. Simply having the executables tells us very little about the system as a whole.
To be honest, a better analogy is that the genetic code is an image of the disk drive, and we do understand the ISA of the processor it's running on. We have no clue what the operating system is, though, nor do we understood the boot process, nor do we even understand what the equivalent of the ELF file format is for this machine.
There's a related problem when you can diagnose a cancer really early -- it's that you wind up, technically, living with cancer for a longer time. Early diagnosis makes treatments look like they're working better and better, when they might not be.
Newer treatments might actually be worse, but early diagnosis makes them look more effective.
Almost every elderly person has cancer. It's just that many people die from something else first before those tiny malignancies grow large enough to cause significant clinical symptoms.
I don't have a firm opinion but tend to agree with you, however...
...an article linked to here on HN many years ago argued that sometimes early detection can lead to downgraded quality of life. The examples they provided were of middle-age men diagnosed with very early stage prostate cancer, which sometimes led to surgery with debilitating complications (like erectile dysfunction, incontinence, and others). The article argued many of those cancers were effectively harmless, that those men would have died of something else after a long life without ever realizing they had cancer, and that the treatment was considerably worse than the disease.
Of course, it could be argued that knowing is always better: that the mistake in those cases was to perform unnecessary surgery.
> The rule of thumb with cancer is that the earlier you diagnose it, the more treatable it is. So yes, please detect cancers as early as possible.
No one argues this is true. But there's mounting evidence that this is less true than one would have believed a couple of decades ago.
* First, as the parent to your post says: if a cancer takes 3 years to go from stage 1 to stage 4, detecting the cancer at stage 1 will increase measured survival by 3 years even if your treatments do nothing.
* Second, the stage at detection is also a measure of how aggressive the cancer is. That is, if you screen every year, and find 100 stage 4 cancers and 100 stage 1 cancers in your population... odds are the stage 4 cancers are much faster growing and more likely to become malignant. You didn't necessarily find them "earlier".
My father just died from lung cancer at 87. It came as a huge surprise, probably masked by other health issues he was having, and was discovered well into stage-4. He was given 6 months, and made it about 4. Watching him deteriorate into a world of pain and eventual confusion is an intensity of human experience I would not wish on anybody going through it first or secondhand.
That being said my family has started to wonder, "when did he first get sick?" as he seemed relatively well until early last year -- other than his other conditions. The best we can come up with is "about a year ago". But looking at this it may have much much earlier. It probably wouldn't have changed the treatment or outcome, 87 is a hell of a run, but from an objective point of view it's very interesting to try to understand when this terrible thing first saw its genesis in him.
"Using rates of mutation as a clock, some of them appear to go back even to before birth - the key JAK2V617F mutation, long associated with these malignancies, is estimated to have shown up anywhere from the 33rd week of gestation up to the age of 11. The DNMT3 mutation, similarly, seems to have appeared from the 8th week of gestation (!) out to about the age of 8."
One of the frustrating things about cancers is that nobody knows the cancer's growth rate, how long from stage 1 to stage 2 etc, when in reality they are just categories, aka "if you have cancerous cells from your liver in your neck, then its stage 4". The problem with this is that no interval of preventative testing can be rationalized. You don't know if once a decade, or once a year, or using your privilege to get tests every 3 months would yield any help in early detection at all! The medical professionals don't know either. "Cancer" is obviously too broad, but even if you have a history of a particular type of cancer in your lineage, you're still at the same issue. We don't know if one cell flips to cancerous and defeats your body's defenses for reproduction all the way to stage 4 within 2 weeks, or whether it is over years.
Knowing that the contributing mutation can be 30-50 years prior is really helpful, and can help doctors authorize the use of their medical facilities more pointedly, while researchers continue to isolate and make peer-reviewable preventative measures that the holistic naturopaths can never do (because they don't do peer review, there may and has been accidentally salvagable parts of their form of medicine).
Actually, you can study these things and see what it does to outcomes, and professionals have.
There's benefits from more frequent screening (and harms, too!). The benefits are tempered by a cancer manifesting at stage 4 could mean:
* You got unlucky with the screening interval and it showed up inbetween, or
* You have a really aggressive cancer that went from stage 1 to stage 4 in a small fraction of the screening interval.
The latter is interesting: if you are screening at an interval, the later stage cancers you find are, on average, more aggressive and faster growing. In turn, spotting them earlier doesn't necessarily lead to better outcomes.
That is: part of the reason why "finding cancer earlier" is associated with better outcomes is that it's easier to find less aggressive cancers earlier.
I think that the best weapon that the general public has against cancer is autophagy, triggered by keeping blood glucose very low at least some of the time. Metabolic changes that can awaken apoptosis might kill many of these mutation carriers.
Since fasting is the best way to induce autophagy, that could explain the apparent negative correlation between cancer rate and a country's food supply [.] http://globalcancermap.com/ [.] https://ourworldindata.org/food-supply
Africa’s average age is half of North America’s, and after controlling for infant mortality still so few other people make it to the much higher life expectancy limit (which is still 10-15 years lower than North America) there that there isnt opportunity for cancer diagnosis to rear up as often! Let alone be tested for cancer to understand if that was an ailment or contributing comorbidity.
I don't think I'm compelled to provide that but I'm open to counter theories
What I'm reading is "hey here is this ailment people get in their 60s, here's this continent where people barely survive until their 60s, do you have a citation for why people there don't frequently get that ailment there? we should really study that"
It would be but it's so, so, ever so hard, to go without even one single meal.
I've stopped evangelizing "fasting" or even shorter intake windows.
If you can't be bothered to skip breakfast for a few weeks just to see how your body responds then let's stop wasting our time and just talk about football or something.
... how 'bout them Cowboys ?!
Huh? You'd be surprised...
But I know a lot of people who cannot skip a single meal and get irritated or angry.
(Of course, it's not that black&white, and not eating at all will quickly deteriorate your health -- I'm just saying that hangriness is not the same as hunger, and learning to differentiate between the two is important)
I think they just need to get used to some poverty for a while.
To me thats what I said, that's what stage 4 means, metastasized.
> I think that the best weapon that the general public has against cancer is autophagy
One can wish
It's not really a wish anymore. There are studies showing this, but I'm too busy to find them for you. Rhonda Patrick at https://www.foundmyfitness.com/ has interviews with various researchers on this topic. Here are some, but this is by no means exhaustive:
https://www.foundmyfitness.com/episodes/autophagy-and-cancer...
https://www.foundmyfitness.com/episodes/cancer-manipulates-s...
https://www.foundmyfitness.com/episodes/caloric-restriction-...
My layman understanding is that healthy cells can withstand the rigors of fasting and fasting-mimicking, but many cancer cells cannot. They die.
If the selective pressure to develop quickly diminishes, then I would expect that uncontrolled growth (cancer) would be less likely as well. It would be interesting to see if this is observable in other animals (those with the shortest development times, which require the fastest bursts of growth, should be at higher risk for cancer or should have evolved solutions like extra telomerases).
https://www.nature.com/articles/nature.2015.18534
Just being alive puts you at risk for cancer.
Most cancer cells are genetically unstable, some mechanisms that usually reduce mutation rates are broken in them. And this enables them to accumulate the mass of mutations they need to actually become cancer.
The most striking hypothesis I read in that chapter was that telomere shortening could actually help a cell to become cancerous. I've no idea whether that idea help up, but it was pretty much the opposite of what I expected. The basic idea is that for cells that have a way to evade the usual stop of cell division for short telomeres, this becomes an advantage. The cells still divide, shortening telomeres so much that it destabilizes the genome. If the cell can survive that, it gains a large amount of the kind of genetic instability that is needed for it to become cancerous.
Shouldn't we have an assembler, compiler, and linker by now? What's taking so long?
It's like trying to understand Linux from just looking at the /bin directory. Simply having the executables tells us very little about the system as a whole.
https://en.wikipedia.org/wiki/Ribosome
Newer treatments might actually be worse, but early diagnosis makes them look more effective.
Prostate cancer is quasi-normal in men over 70 and usually grows so slowly that it does not influence their lifespan.
Pancreatic cancer is deadly at any age and its treatment would profit a lot from very early detection.
...an article linked to here on HN many years ago argued that sometimes early detection can lead to downgraded quality of life. The examples they provided were of middle-age men diagnosed with very early stage prostate cancer, which sometimes led to surgery with debilitating complications (like erectile dysfunction, incontinence, and others). The article argued many of those cancers were effectively harmless, that those men would have died of something else after a long life without ever realizing they had cancer, and that the treatment was considerably worse than the disease.
Of course, it could be argued that knowing is always better: that the mistake in those cases was to perform unnecessary surgery.
No one argues this is true. But there's mounting evidence that this is less true than one would have believed a couple of decades ago.
* First, as the parent to your post says: if a cancer takes 3 years to go from stage 1 to stage 4, detecting the cancer at stage 1 will increase measured survival by 3 years even if your treatments do nothing.
* Second, the stage at detection is also a measure of how aggressive the cancer is. That is, if you screen every year, and find 100 stage 4 cancers and 100 stage 1 cancers in your population... odds are the stage 4 cancers are much faster growing and more likely to become malignant. You didn't necessarily find them "earlier".
Maybe it's stage 1 because you got lucky and saw it early. Maybe it's stage 1 because it grows really slowly and will be stage 1 still in 5 years.
Only way you could know is to not treat and watch what happens... Everything else is a fudge.
That being said my family has started to wonder, "when did he first get sick?" as he seemed relatively well until early last year -- other than his other conditions. The best we can come up with is "about a year ago". But looking at this it may have much much earlier. It probably wouldn't have changed the treatment or outcome, 87 is a hell of a run, but from an objective point of view it's very interesting to try to understand when this terrible thing first saw its genesis in him.