Showing posts with label Knudson. Show all posts
Showing posts with label Knudson. Show all posts

Monday 1 September 2014

The Knudson Multiple Hit Hypothesis in Cancer, leading to the emerging Peter Multi-Mutation Matrix Theory of Autism

In Autism the more complicated research and emerging diagnostic tools seem mainly to relate to things like genes and CNVs (Copy Number Variants).  To understand this in detail, a PhD in genetics might be helpful; but once you realize that nobody fully understands this emerging area of science, we may still be able to draw some usable insights, that have not been noticed by the autism research community.

The focus of research is on cancer; autism remains in a backwater.  However, what research there is on autism and genetics does seem to show rather more overlap with the mechanisms and pathways seen as being behind cancer than you might have expected.  This, combined with the very odd sounding finding by that Nobel Laureate at MIT, that neither cancer nor autism can develop without the presence of a substance called PAK1, makes me interested to look at the cancer research.

Then you notice after only a few minutes of research, that there are numerous instances where cancer and autism share common “abnormalities”, including:-

·        PTEN a protein that is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers. PTEN acts as a tumor suppressor gene.

·        Tumor protein P53, known as the “guardian of the genome" because of its role in conserving stability by preventing genome mutation.

We have the fact that in autism there are numerous abnormalities in various human growth factors, which again has overlaps with irregular cell mutation/proliferation in cancer.  These same growth factors are implicated in aberrant mTOR behavior, another target of cancer research.

In addition, two conditions involving tumors, often in the brain, are comorbid with autism, namely Neurofibromatosis and Tuberous Sclerosis Complex (TSC).

Can so many links in the mechanisms behind cancer and autism be coincidence?

While I do like to think of autism in terms of my earlier Venn diagram,

there will be another way to look at autism, which will look quite different.  It will be a list of genes whose function has been either been completely disrupted, partially disrupted or not affected. This matrix would then define a person’s unique autism phenotype.

It will be a long list of genes and so there will be many thousands of possible permutations, explaining why each person with autism seems to be unique.  When you have met a person with autism, you have done just that, met one person.  The next one will be distinctly different, but still be labeled autistic.

Some of these genetic abnormalities were rare “de-novo” mutations, other were inherited from the parents, some came from epigenetic disruption either in-utero, after birth, or indeed from earlier generations (we save seen how epigenetic changes can be passed through the generations).   This epigenetic change is the mechanism whereby the environment, what you eat, where you live and how you live, may affect both your genes and those of your successors.

As the number of mutations exceeds the adaptive capacity of the brain, then strange dysfunctions will appear.  When taken together, these dysfunctions appear as what we call “autism”.  Some single gene mutations are sufficient to produce autism, for others further genetic damage may be needed.

So the link with cancer seems to be about the control of mutations.

There are many very clever people whose working lives are dedicated to cancer research, so I doubt we will be able to out-smart them.

When it comes to autism research, I am much more optimistic that there are likely many unturned stones and unnoticed or lost connections.  So I expect there will be little gems among the PAK inhibitors, mTOR inhibitors etc.

Back to Cancer

Today’s post will not be complicated; it is more about common sense, a Finnish amateur historian and a thoughtful cancer researcher called Alfred Knudson.  Some variants of “their” cancer hypothesis are now being applied to autism.

First Came Nordling

The origins behind Knudson’s cancer hypothesis, rather surprisingly, come from the work of a Finnish architect with an interest in history and statistics, called Carl Nordling.
His multi-mutation theory on cancer was published in the British Journal of Cancer in 1953. He noted that in industrialized nations the frequency of cancer seems to increase according to the sixth power of age. This correlation could be explained by assuming that the outbreak of cancer requires the accumulations of six consecutive mutations.

Then Came Knudson

Later, Knudson performed a statistical analysis on cases of retinoblastoma, a tumor of the retina that occurs both as an inherited disease and sporadically. He noted that inherited retinoblastoma occurs at a younger age than the sporadic disease. In addition, the children with inherited retinoblastoma often developed the tumor in both eyes, suggesting an underlying predisposition.

Knudson suggested that multiple "hits" to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two "hits" had to take place before a tumor could develop, explaining the age difference.

It was later found that carcinogenesis (the development of cancer) depended both on the activation of proto-oncogenes (genes that stimulate cell proliferation) and on the deactivation of tumor suppressor genes (genes that keep proliferation in check). Knudson's hypothesis refers specifically however, to the heterozygosity of tumor suppressor genes. Simply proposing that a mutation in both alleles is required, as a single functional TSG is sufficient.

The Two-Hit Theory of Cancer Causation

Now to Apply the Multiple Hit Model to Autism

In the case of cancer it has been found that for mutation to occur it is necessary for two genes to be activated/deactivated.  The first gene is activated and tells the cells to proliferate; the second gene that should be stopping the cells proliferating has to be turned off.  Both genes have to malfunction for cancer to be possible.
In the following, science heavy, autism paper they conclude that the data suggests a “Multiple Hit Model of Autism Spectrum Disorders”.

It also suggests that some of the gene mutations are doing damage, while other mutations are actually positive, trying to counteract the effects of the damaging mutations.

“Finally, our analyses suggest the interesting possibility that deleterious mutations of neuronal genes (e.g. SNTG2 and MYT1L) could potentially counteract the effect of synaptic deleterious mutations (e.g. SHANK2). The identification of risk and protective alleles within the same subject is one of the main challenges for understanding the inheritance of ASD.

Coming back to the “easier” research, which comes from psychologists rather than geneticists, takes us to a paper about those people with autism who do not fare well during and after puberty.

Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a “first hit” that sets up a neural system that is “built to fail” in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the “second hit” that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence.

Double-tap Autism

Regular readers may recall a recent post about what I termed Double-tap autism.

The second tap was not adolescence, rather a viral infection in early childhood, occurring in someone with classic early onset autism.

The Peter Multi-Mutation Matrix Theory of Autism

There will of course have to be a Peter Multi-Mutation Theory of Autism and it will necessarily have to include therapeutic implications.  Hopefully, it will show that once sufficient mutations have been pharmacologically countered, the adaptive capacity of the brain may be able to overcome those that are left.

It does appear from the research that some mutations are occurring to counter the effect of the damaging mutations, perhaps in a form of self-repair process.

To establish exactly what has happened in any individual the best way would seem to be through proteomics, which is the science surrounding how genes produce the various proteins that actually give them their biological effect. By analyzing the various proteins you can see what genetic mutations have actually happened, as opposed to analyzing the genes themselves that would tell you only what might happen.  

Also, by genetic testing, to what extent can you detect genes that have been only partially disrupted?