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All Roads Once Led to Rome… But Do All Roads Lead to Autism??

Even though, at face value, cancer and autism may seem like worlds apart, if you take a look at their respective genetics you may find more similarities than you bargained for. And because in many ways the field of autism research trails behind that of cancer research, we may be able to learn quite a lot from the other.

In a recent article by Lawrence et al. (2013), the team studied lung squamous cell carcinoma, reporting that 450 allelic variants occurred at a significantly higher frequency in the tumor samples as compared to normal controls. Of those genes, the researchers noted that:

The research team went on to study other cancer types, each returning very similar results as the lung carcinoma samples above.

The point of the research wasn’t to study mutations in lung cancer however. Though the results of course included genes which have known relationship with tumor development, the researchers expressed concern over a significant portion of the results, declaring that,

“…many of the genes seem highly suspicious on the basis of their biological function or genomic properties”.

Thus, the entire point of the study was to draw attention to the fact that genetics studies in the field of cancer research have reported many strong-association genes with dubious ties to cancer development. The olfactory receptors, for instance, play a doubtful role in the progression of lung cancer considering their general function as chemoreceptors for olfaction. In addition, even though OR genes tend to be quite small in length, they frequently house repetitive sequences which may simultaneously explain their higher rates of mutation as well as their genetic diversity (–there’s a HUGE number of OR’s in mammalian genomes) [1].

Larger genes, including those with large coding sequences or introns, are often characterized by higher mutation rates (hence the larger size due to more expansions and mobile element insertions) and are frequently located at or near common fragile sites [2]. (Just as an interesting aside, approximately 40-50% of genes lie very near fragile sites, indicating that gene location is not randomized and probably shares its origins with the biologic function of fragile sites.)

So what does this mean? As Lawrence et al. suggest, OR and large genes may have higher rates of mutation in general. Therefore, specific precautions need to be taken in scientific analysis to account for the varying rates of mutations across genes in order to avoid false positives in cancer research. They state quite clearly that they believe a large number of genes which have reportedly been associated with various types of cancers are in fact not causally related to the conditions but are, in short, coincidental. Especially in the case of a disease like cancer which is characterized by a progressively disturbed and destabilized genome.

Autism. What does autism have to do with cancer? At the moment, my ideas are still somewhat vague. However, I suspect it isn’t coincidence that those findings which predict false positives in the Lawrence et al. study are also extremely common in autism. For instance,

Starting to sound familiar? Many of the same genes which are turning up as false positives in cancer studies are also turning up in autism research. The difference is that we in the autism research community haven’t yet addressed whether these genes are false positives or not.

It truly begs the questions:

  1. How many false positives might we be receiving in our research, especially those mutations which are reproducible across studies?

  2. Are these highly mutable genes like CNTNAP2 causally associated with the condition, or are they merely coincidental because they’re more mutable?

  3. And if they are coincident, why do these mutations occur more frequently in autism versus controls? It’s not as if autism is a cancer that exhibits progressive genetic instability.

What with our lack of an autism biomarker, interpreting these results are especially confusing because genes relating to the nervous system are often large, unstable, and located near fragile sites, all characteristics which should make one cautious about overstating a relationship to autism or any other neurodevelopmental condition in which they may inevitably arise more often [2]. And because we don’t have a proper definition for autism beyond a behavioral syndrome– in other words, we don’t really understand what’s occurring in the brain to create the behaviors– then any mutations that are brain-related are inevitably thrown onto the list of “possibles”. And it is a very, very long list indeed. It includes numerous proliferative and motility factors, adhesion molecules, transcription factors and regulators, synaptic molecules, just about any kind of neurotransmitter you can think of (glutamate, GABA, serotonin, dopamine, acetylcholine, etc.), redox agents, you name it.

As the title of the post says, all roads once led to Rome, but do we honestly believe that all roads lead to autism? I have my doubts. But until we have a better definition of what’s occurring in the developing autistic brain, I guess we can’t really know for certain.

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