by Anicka AbiChedid
Imagine you are at your desk, typing on your computer. It’s 11 PM at night, and you’ve got an essay due at midnight. Naturally, you’re feeling a bit stressed and tired, leading to typos in your essay. Thanks to your computer having specific tools, such as autocorrect, you can fix those typos and continue writing.
Each cell in our body has the ultimate goal of making more cells, and to do so, it is tasked with faithfully copying its DNA each time it divides. To sustain all of the activities a cell must perform in its lifetime, the DNA must be copied correctly. The cell usually gets it right the first time, but just as we can make typos when we’re stressed writing our essays, cells can make typos in their DNA. Thankfully, every cell in our body comes equipped with its own version of autocorrect, called “mismatch repair.” Mismatch repair identifies typos in the DNA and swaps out the typo for the correct letter.
When DNA repair pathways responsible for fixing damaged DNA are overwhelmed, this leaves behind distinct changes in the DNA. With the development of whole-genome sequencing, scientists use this technique as a magnifying glass for DNA, uncovering the precise sequence of each cell’s DNA. Researchers at the Wellcome Sanger Institute, a leading cancer research institute, used this technique to discover that cancer-causing agents leave behind a set of characteristic typos in the DNA, termed a “mutation signature.” Certain processes, like tobacco smoking and UV exposure, leave behind distinct, characteristic patterns of typos on the DNA. By sequencing tumors across many patients, scientists created a platform of over 30 mutation signatures corresponding to distinct causes, a remarkable tool that changed the cancer research landscape (Figure 1). We continue to discover new mutational signatures, which you can learn more about here.
Figure 1. Detection of mutation signatures in tumor cells identifies their underlying source. Created by author with BioRender.com.
Sometimes, people are born with cells that lack mismatch repair (a condition called Lynch syndrome). This means that many mutations can’t be fixed, leaving behind its own characteristic pattern of DNA mutations. DNA comprises four components, abbreviated by the letters A, C, T, and G. These components come in pairs: A matches with T, and C matches with G. When mismatch repair is missing, the cell will mistakenly place a C where a T belongs. Likewise, when a T is needed, the cell mistakenly places a C instead (Figure 2). Coupling this defined pattern of typos made in the DNA with advanced sequencing methods allows physicians and researchers to determine the underlying causes of errors made in the DNA of cancer cells.
Figure 2. DNA base substitutions created in the absence of mismatch repair. Created by author with BioRender.com.
When mismatch repair is missing, individuals are at risk for specific types of cancers, including colon and endometrial cancers. Cancers with mismatch repair deficiencies respond to immunotherapy treatments because the immune system better recognizes cells with large amounts of mutations. Physicians and researchers in the clinic can now sequence tumor DNA, analyze the pattern of mutations, and tailor treatments toward those findings.
Edited by Yasemin Cole, MD PhD Student, UNC School of Medicine
Anicka AbiChedid is a Ph.D. student at Duke University studying the origins of mutation signatures in tumor cells. Anicka is passionate about working toward making science more accessible to the public.
