
The human body is a mosaic of different genomes - pseudolus
https://www.nature.com/articles/d41586-019-01780-9
======
echelon
We all have tiny little cancers right now. Our bodies are constantly producing
mutations that disable growth regulation, promote proliferation, change cell
adhesion, etc.

It's just that our body is programmed to defeat these irregularities and
disease states. The immune system is a major component, as it can recognize
cell surface epitopes of a variety of types - mutated ones, or even suicide
signals. Cells that detect that they have entered a disease state will often
enter apoptosis or tell their neighbors about it.

We get cancer when cells accumulate so many mutations that they not only grow
unchecked, but they also evade the body's natural forms of detection and
clearance. And then they eventually hill climb into a state where they leave
their original tissue and move about the body uncontrolled.

You evolved to defeat cancer. It's just a numbers game until one of your
precancerous cells accumulates enough mutation to escape capture.

~~~
will_brown
I recall reading a study describing cancerous/mutated cells very similarly. I
don’t recall exactly but the study was in regards to diet (maybe specifically
vitamins/minerals or antioxidants) that promoted detection (again I don’t
recall but maybe by the immune system).

As I remeber the diet not only was supposed to improve detection but response
and I think the improved response included the body releasing other cells
(again I don’t remember but think fat cells, although that doesn’t sound
right) to surround/isolate/starve the cancer cells, so in a best case the
cancer cells would die and if they wouldn’t die then they would not be
permitted to grow/replicate/freely travel.

Does this ring a bell to you vis-a-vis any diet?

~~~
echelon
Nothing has been proven, but it's hypothesized that chronic inflammation (and
the foods that can cause it) are bad and can lead to the development of
cancer.

Here's a review article on the current understanding: [https://translational-
medicine.biomedcentral.com/articles/10...](https://translational-
medicine.biomedcentral.com/articles/10.1186/s12967-018-1448-0)

~~~
perl4ever
I wonder if saying "chronic inflammation can lead to the development of
cancer" is like saying "being dumb can lead to not being smart". Chronic
inflammation is obviously immune system dysfunction, and cancer is also immune
system dysfunction. Perhaps the same process could be described with either
term at some point in time, but is that an explanation of anything?

------
hprotagonist
In retrospect this shouldn’t surprise anyone, but it still feels like a
radical departure from the more or less cute stories we are taught in intro
Bio.

Biology is fractally weird and emphatically deals in probability distributions
not binary classes. You can and should always expect an “except...” clause at
the end of any declarative statement about a biological system. If it’s not
there explicitly, it’s implicit.

Confusing the map (“individuals have unique DNA”) for the terrain (“...except
for here and here and maybe over there, especially if you look really hard”)
is always a risk.

Being able to know which map to use for which terrain (i.e., do we need to
care about mosaics for this problem or not) is, more or less, the reason we do
research.

~~~
wpasc
Are mutations in DNA arising from truly random events? When I say random, I
mean outside of the knowability of Laplace's demon?

I know quantum mechanics contains true randomness, in the creation of DNA
copies does this randomness contribute?

~~~
astazangasta
They are definitely not random. Sequence context matters a lot - e.g. in
humans CG mutates about 10x more often than other dinucleotides. Other
contexts also contribute - genes that are expressed more are more mutable, and
so on.

------
apathy
Also worth noting: this is further evidence that cancer, like many other
diseases, is in part an immune disease.

When central tolerance is too lax, tumor cells can more easily survive a trip
through the bloodstream to seed metastasis (the eventual cause of nearly all
cancer deaths, aside from treatment sequelae and thrombosis).

By contrast, if central tolerance is overly tight, then you see autoimmune
diseases (severe aplastic anemia is a classic example) where the immune system
wipes out the competition from healthy progenitors, and mutant clones better
able to survive the onslaught seed cancers. This is one reason why both
immunosuppressive therapies and immunostimulatory agents can both increase
cancer risk.

It’s also worth noting just how different the mutational profiles of pediatric
tumors are versus adults. To grossly oversimplify, peds tumors tend to carry
mutations (typically gene fusions, amplifications, or deletions) that confer a
developmental-stage-specific advantage in proliferation, such that no normal
progenitor could ever hope to keep up. By contrast, the most frequently
observed point mutations in adult cancer (to TP53, in particular, although
DNMT3A in leukemia is another example) confer stress resistance to the mutant
clones. They are nearly absent from tumors seen in children. Even Li-Fraumeni
syndrome, where people carry deleterious TP53 variants inherited from their
parents, does not begin to show a huge risk differential until adolescence. So
there are evolutionary, developmental, and immune differences that shape the
genesis, selection, and growth of different tumors in different age groups,
and tend to indicate different treatment.

The standard chemo regimens for pediatric ALL (acute lymphoblastic leukemia,
the most common cancer in kids) would kill many adults, and despite over 90%
cure rates in kids, far less than half of adults with the “same” disease will
survive it. (In quotes, because as with every other tumor that spans the full
range of age groups, the drivers in adults are different from those in kids
for almost all instances).

Similarly, immune checkpoint inhibitors can generate miraculous responses in
adults tumors, though these are seldom seen in pediatric patients. With the
benefit of hindsight, it’s more obvious why this is so (the random
accumulation of mutations over decades in adult tumors is more likely to
generate immune-recognized non-self proteins), but it took a long, long time
to get here. (Look up “Cooley’s Toxins” if you think immunotherapy is new :-/)

I still find the fields fascinating, despite having enough ghosts on my
conscience to stock a mausoleum. Cancer is part of our evolutionary heritage;
the best we can do in adults is usually try to control its spread and cut out
enough of it for the immune system to mop up the rest. Kids are different, but
that’s another story for another time. It’s a great period in history to be
working on understanding these things and they interact.

~~~
rolltiide
> Also worth noting: this is further evidence that cancer, like many other
> diseases, is in part an immune disease.

I think about that sometimes but from the lens that perhaps there is an
additional state that cancerous cells are preventing from occurring.

"We cured cancer, but then the worst appeared"

~~~
apathy
Dubious — cellular senescence (whether proliferation- or oncogene-induced) is
the usual failsafe for avoiding proliferation of damaged cells. It relies
heavily upon TP53, RB1, and CDKN2A, all of which are routinely deleted in
tumors. When anti-aging researchers refer to senolytic drugs, usually they’re
referring to drugs that clear senescent cells.

Oddly, the drugs tend to clear out tumor cells in many cases, as senescence
bypass is a critical step in carcinogenesis.

Not oddly, the inflammatory paracrine (secreted) profile of senescent cells
tends to engage the immune system in clearing them out. Immunosenescence gets
in the way of this and also of clearing precancerous cells, hence it is a risk
factor for both age-related frailty and cancer.

