Finding DNA mutations that drive cancer development and growth can be akin to finding Waldo, the plucky 80’s cartoon lad wearing red and white stripe clothing and glasses hidden amongst a plethora of quirky characters.

One strategy to find the cancer-driving mutations involves analyzing DNA directly from tumors. If a particular mutation keeps popping up, then it is concluded that the mutation may be giving a competitive edge in allowing a cancer cell to proliferate and grow. Hence, the term “driver” mutation. As it turns out, this strategy only rarely identifies true cancer driving mutations.

One example of such a false driver mutation arose in a recent study of esophageal tissue. Two research groups probed for mutations that drive esophageal cancer (Martincorena et al., 2018; Yokoyama et al., 2019). They learned that the genes most often mutated in the healthy tissue were from the NOTCH family, set of proteins that are vital in embryo development, determining the fate of stem cells, suppression of cancer, promotion of cancer, etc. (Hori, Sen, & Artavanis-Tsakonas, 2013). The two groups also reported that the mutations were known cancer-driving mutations. Yet, no cancer cells or tumors were present.

Just how can mutations potentially mislead? Well, as in the previous example, the mutations may just be acquired with age. In another case, the misleading mutations may be attributed to the actions of a protein. Yep. A protein can create Waldo look-alike mutations and make scientists think they are looking at a legit mutation that drives cancer. How? During DNA replication, DNA takes on a shape that is just too irresistible to the APOBEC3A protein (Buisson et al., 2019). This protein binds to the DNA shape and introduces a mutation. Upon searching the genome, these tantalizing sites occur in numerous places and not just sites labelled as the Waldo driver mutations. If they are occurring in sites previously labelled as driver mutations, are they now really Waldo-esque seahorses?

If anything, these examples show that identifying true mutations that will lead to cancer is not trivial. They also raise a worrisome question: If false driver mutations popup and misdirect cancer researchers, what are the chances it is also happening in other diseases or conditions where researchers are trying to determine health risks from peoples’ DNA?

 

References

Buisson, R., Langenbucher, A., Bowen, D., Kwan, E. E., Benes, C. H., Zou, L., & Lawrence, M. S. (2019). Passenger hotspot mutations in cancer driven by APOBEC3A and mesoscale genomic features. Science, 364(6447). doi:10.1126/science.aaw2872

Hori, K., Sen, A., & Artavanis-Tsakonas, S. (2013). Notch signaling at a glance. J Cell Sci, 126(Pt 10), 2135-2140. 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. 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. doi:10.1038/s41586-018-0811-x