EpilepsyandAutismlogonew2Individuals diagnosed with autism spectrum disorder (ASD) have much higher rates of oncogenic mutations but, paradoxically, have substantially lower rates of cancer, a finding that may lead to cancer therapies being “repurposed” to treat autism.

In a two-part study involving a genomic database analysis, investigators initially found that autistic individuals have markedly increased rates of DNA mutations in genes associated with the development of cancer.

However, a retrospective analysis of more than 12,000 patients showed that younger individuals with ASD in particular are more than 90% less likely to develop cancer, an effect that is more pronounced in females.

Lead researcher Benjamin Darbro, MD, PhD, assistant professor of medical genetics in the Stead Family Department of Pediatrics at the University of Iowa Carver College of Medicine, Iowa City, told Medscape Medical News that his team is “very excited” about the findings.

Although the nature and impact of the mutations and their relationship to cancer risk has yet to be established, the research “does provide what we hope to be a very promising direction in research, which is this idea of using, or repurposing, medications or treatments that have been developed for targeted cancer therapy as a way of potentially modulating the neurodevelopmental phenotype in conditions like autism or even intellectual disability.”

The research was published online March 2 in PLOS ONE.

Lower Risk in Females

Initially, investigators selected a series oncogenes and tumor suppressor genes from various databases and reviews, along with genes for conditions such as ASD, intellectual disability, epilepsy, skeletal dysplasia, dilated cardiomyopathy, retinitis pigmentosa, and nonsyndromic hearing loss.

They then compared data on the frequency of rare, nonsynonymous, coding, single-nucleotide variants in ASD patients from the ARRA Autism Sequencing Collaboration with that from the Exome Variant Server database.

Results showed there was a nonsignificant increase in the number of rare coding variants in tumor suppressor genes in individuals with ASD in comparison with control persons (P = .20). There was, however, a highly significant increase in the number of rare coding variants in oncogenes in the autism cohort compared with control persons (P < 1.0×10-8).

There was no significant difference between ASD individuals and control persons in the number variants in genes for skeletal dysplasia, dilated cardiomyopathy, retinitis pigmentosa, and nonsyndromic hearing loss, which, the researchers note, indicates that the finding for oncogenes was not due to a population matching error or other technical artifact.

The researchers then retrospectively examined rates of neoplasms among 1837 autistic patients and 9336 control patients at the University of Iowa Hospitals and Clinics.

This showed that, overall, cancer was significantly less prevalent in autistic patients vs control patients, at 1.3% vs 3.9%, with an odds ratio of 0.33 (P < .0001). Interestingly, the difference in cancer rates was greatest among the youngest patients, at 0.3% and 3.3% respectively, in autistic patients vs control patients aged 0-14 years.

Further analysis revealed that the odds ratio of cancer among autistic patients vs control patients aged 0–14 years was 0.06 (P < .0001); it rose to 0.35 among patients aged 15-29 years (P = .024), 0.41 in those aged 30-54 years (P = .095), and 0.49 in those aged 55 years and older (P = .267).

The reduction in cancer risk in individuals with autism was greater in females than males, at respective odds ratios of 0.13 and 0.50 (P = .005 for both). The researchers found that the greater cancer risk reduction was in girls aged 14 years or younger, at 97%, and the smallest reduction was in men older than 55 years, at 5%.

The team verified the validity of the findings by establishing the rates of diseases such as diabetes mellitus, hypertension, atopic dermatitis, esophageal reflux, and allergic rhinitis between autistic patients and control patients. No significant differences were found.

Invisible Elephant in the Room

Discussing the findings, Dr Darbro acknowledged that the baseline rates of cancer among children are low and that it is possible that unknown environmental factors could be playing a role in the associations.

“Environmental factors are always the invisible elephant in the room, if you will, in that they could always be playing a role in pretty much any kind of genetic study, and that is one of the limitations of this particular study. We really don’t have a lot of mechanisms to account for some of that environmental influence,” he said.

One outstanding question is why the reduction in cancer risk with autism decreases with advancing age.

“It’s not real clear to us yet whether or not that decreasing in the protective effect is truly biological or could be a bit of an artifact of the lower sample size that we have at those higher age ranges,” Dr Dabro noted.

To answer this and other questions, the researchers hope to replicate the results in other populations from different medical centers across the United States. They also want to conduct a prospective study to monitor the incidence of cancer in ASD patients aged 5 to 10 years.

For Dr Darbro, one of the most intriguing aspects of the study is that of the nature of the oncogenic DNA mutations that are overrepresented in ASD individuals.

“We found that there were a lot more of [the mutations] in the autistic population than in the control population, but we haven’t yet really dissected out what effect many of these mutations are having,” he said.

He noted that in oncogenesis, what typically drives the development of cancer is that genes become mutated, and then “they are in a sense being ‘turned on,’ and they are being turned on at abnormally high levels, and that’s what’s driving cells to become cancerous.

“With the variations in the mutations that we’re finding in patients with autism, it’s not clear, based on just the mutation itself, whether or not these are the types of mutations that would turn on the gene, or would turn off the gene, or maybe even allow it to be turned on but functioning at a much lower level.

“That, I think, is going to help really to establish what that mechanism is behind having greater mutations in these genes and having a lower cancer risk,” he said.

Source: Medscape, written by L. Davenport
This work was funded by the National Heart, Lung, and Blood Institute. The authors report no relevant financial relationships.