How much is too much? According to author Douglas Adams, the answer to all life’s questions is 42. It seems to work as an answer in any situation, such as “How many lemon curd-filled donuts are too much for me?”

“How much is too much?” is a good question to ask even in genomics. For example, how many mutations are too much and will give me cancer? In this case, however, “42” may not be universally correct.

The conventional – and logical – understanding of the link between mutations and cancer centers around the notion that once a cell has acquired enough mutations in key genes it will lead to a cancerous tumor. But is this really correct? Two research groups have recently provided evidence that will challenge your perception of the “logical” genomic galaxy (Martincorena et al., 2018; Yokoyama et al., 2019). Don’t panic and grab your towel!

The two teams set their sights on the esophagus, particularly the layer of cells that lines it, to better understand the underpinnings of cancer development. Not too surprisingly, both groups noted that the number of mutations increased with age and promoted cell proliferation. But they also noted several peculiar observations.

First oddity: Martincorena et al. reported that the cells lining a healthy esophagus possessed more mutations in cancer-associated genes than human skin cells, though fewer mutations overall. (This difference in overall rate is not surprising when you consider that skin experiences a lot of exposure to UV light, which directly causes mutations in DNA.) They also saw that the healthy esophaguses carried about 200 mutations per cell in young adults and over 2000 per cell in older adults. Yet, no cancer of the esophagus was detected in these people. Yokoyama et al. also saw an increase in mutations in older populations.

The second oddity noted had to do with the genes most often mutated in healthy esophaguses, which happen to be from a defined group known as the “NOTCH family.” These genes code for critical proteins that resemble contorted chains bedazzled with various modifications (Hori, Sen, & Artavanis-Tsakonas, 2013). The types of modifications present can dramatically change the way NOTCH proteins relay important messages to surrounding cells. These lines of communication are vitally important for embryo development, determining the fate of stem cells, suppression of cancer, promotion of cancer, etc.

Both research groups noted that the mutations found in the NOTCH genes are known to drive cancer growth. But cancer was not detected in the individuals carrying the “driver mutations.” Obviously, something beyond the gene is at work here.

Face it, our genomic galaxy is bizarre. The further into it we get, the more bizarre it gets. With the complexity of genomics, we may never truly know how many or what exact mutations will definitely cause cancer (though maybe 42 will be the answer in a few cases). Hang on to your towels as we continue to hitchhike through the human genome.

 

References

Hori, K., Sen, A., & Artavanis-Tsakonas, S. (2013). Notch signaling at a glance. J Cell Sci, 126(Pt 10), 2135-2140. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23729744. doi:10.1242/jcs.127308

Martincorena, I., Fowler, J. C., Wabik, A., Lawson, A. R. J., Abascal, F., Hall, M. W. J., . . . Jones, P. H. (2018). Somatic mutant clones colonize the human esophagus with age. Science, 362(6417), 911-917. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30337457. doi:10.1126/science.aau3879

Yokoyama, A., Kakiuchi, N., Yoshizato, T., Nannya, Y., Suzuki, H., Takeuchi, Y., . . . Ogawa, S. (2019). Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature, 565(7739), 312-317. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/30602793. doi:10.1038/s41586-018-0811-x