Allison Johnson ’20 and Maria Tjilos ’20

Cancer is one of the most prevalent diseases that plagues our society. According to the National Cancer Institute, around 38% of people will be diagnosed with some form of the illness during their lifetime. Given this, almost every individual has either had their life uprooted by cancer, or knows of someone who has been personally affected. The burden of this disease expands past the emotional and financial turmoil experienced by an individual, and also has a large impact on our society as a whole. In 2017, an estimated $147.3 billion was spent in the United States alone for cancer care (National Cancer Institute). This price is expected to continuously rise due to a large aging population, an increase in diagnoses, and new, more expensive treatments being developed.

Since there are numerous types of cancer, each with their own method for proliferating, differing diagnoses may require a unique treatment. One technique that is continuously used for most forms and stages of cancer is chemotherapy. While this treatment has several side effects, including nausea, hair loss, and fatigue, one that is increasingly gaining attention is chemo brain. Chem brain is characterized by changes in cognitive functioning, including deficits in learning and memory, attention, and concentration6. Although there are many possible causes for this change in brain function, a possible mechanism researchers have begun to focus on are changes in the reading of genetic material following chemotherapy treatment.

While there are many ways to treat cancer, chemotherapy is one of the most common and well-known therapies. The goals of chemotherapy can range from destroying cancer cells, controlling their division, or to control the symptoms of the cancer itself (WedMB, n.d.). Chemotherapy achieves these goals through disrupting the cell division process or causing cell death2,1. It’s often administered via an IV, but can also be administered into the cerebrospinal fluid or taken orally. Chemotherapy is often paired with other forms of cancer therapy, such as radiation or surgery1. There are off-target effects associated with chemotherapy, such as hair loss and nausea, because it can also affect or harm healthy, non-cancerous cells. A new off target effect is being discussed in the community as 35% of patients report suffering from chemobrain6. Chemobrain differs from other off target effects, as it’s not outwardly physical and it occurs after, not during, treatment. It involves changes in cognitive function that lead to issues with learning, memory, attention, and concentration that are persistent and long-lasting, ranging from months to years after receiving treatment6. Research on chemobrain points to neuronal injury following treatment that results in incorrect repair and remodeling of the brain: more specifically, epigenetics.

As pictured in the image above, chemotherapy treatment has vast effects throughout the body, and is not limited to areas where cancerous cells are present (Hyunsoo, 2019).

Epigenetics is an umbrella term encompassing any changes to the 3-D structure of DNA that influences gene expression and organization; epigenetics does not change the physical sequence of DNA, but rather its arrangement in space. One can think of epigenetic modifications in terms of footnotes in a book; the changes that take place help guide a reader interpret what they are reading but do not change the text itself. There are many ways that our cells use epigenetic mechanisms to control gene expression. A common way that cells use epigenetic mechanisms to control gene transcription is through DNA methylation. This is the process of adding a methyl group, a sort of chemical tag, to cytosines, a building block of DNA, in the DNA code. This epigenetic mark is associated with decreased expression of genes, although in some circumstances can act as an enhancer for gene expression. Another common way that cells use epigenetic mechanisms to control gene transcription is through histone modifications. Histones are a part of the broader chromatin complex, and DNA wraps tightly around these histones in the nucleus. When the DNA is wrapped tightly, cellular machinery is unable to access the DNA sequence. On the other hand, the DNA can unwind from around the histone and cellular machinery responsible for reading the DNA sequence can access the information needed to express the genes. The cell can modify these histones by adding different molecular markers to either encourage gene expression or discourage gene expression. These modifications include acetylation, methylation, ubiquitination, and phosphorylation (Sweatt et al., 2016).


The top schematic shows the effect of DNA methylation on gene expression. To the left, gene expression is present due to the lack of DNA methylation, while to the right, gene expression is repressed due to methyl groups being present9. The bottom schematic shows acetylation of histones which are the proteins DNA wraps around. This permits more room for transcription of DNA to take place and results in increased gene expression8.

In regards to chemobrain, this paper will only discuss the acetylation and methylation of histones. While other modifications may occur following chemotherapy treatment, a larger body of research focuses on the changes on the histone acetylation and methylation that takes place. Acetylation of histones is one of the most common activating epigenetic marks the body uses to control gene expression. Acetylation increases the transcription of DNA by loosening the tight compaction of it around the histones and making it easier for the transcription machinery to access the DNA. Histone deacetylases (HDACs) are the enzymes responsible for adding this activation mark at a specific amino acid, lysine. These marks are reversible and can be removed if needed. Methylation of histones also occurs at lysine residues, as well as arginine residues, but is more complex and has more variation in its results. These marks can activate or repress gene transcription depending on where the methylation mark is added (Sweatt et al., 2016).

The primary focus of inquiry in the field of chemo brain and epigenetics is what modifications are taking place following chemo treatment. An important caveat to explore relating to this is the possible sex-differences that take place. Kovalchuk and her team explored this using rodents, and paid particular interest to the prefrontal cortex, an important brain region for decision making and attention, along with the hippocampus, which is home to learning and memory3. In the study, mice were administered either cyclophosphamide (CPP) or mitomycin C (MCC), two different drugs used for chemotherapy treatment, which are toxic to living cells. Researchers found that the most notable changes in gene expression took place in the prefrontal cortex of females who received MCC treatment. In the same female animals, MCC induced a decrease in DNA methylation across the genome, meaning that genes were able to be more easily read. In addition, mice exposed to MCC experienced changes in the brain resembling an aging brain. Alterations also occurred for those receiving treatment with CPP, with altered expression in the hippocampus noted. However, the results from this study indicated the prefrontal cortex of female mice to be the most vulnerable, with lowered DNA methylation and decreased DNA methyltransferase activity3.

Another study by Kovalchuk et al. investigated the possibility of chemotherapy having transgenerational effects, or carrying changes over to one’s offspring4. Specifically, researchers were interested in whether male rodents receiving “chemotherapy treatment” passed on the effects of chemo brain to their offspring. Again, the researchers used cyclophosphamide (CPP) and mitomycin C (MMC), along with procarbazine (PCB), all of which are chemotherapy treatment drugs, to assess the alterations in protein expression and DNA damage. Following exposure to MMC and PCB in fathers, levels of a protein that works to maintain levels of DNA methylation during replication of DNA decreased in the offspring. This means that a change in expression of this protein could alter the DNA methylation of the children’s genome. Additionally, the researchers noted decreased levels of a protein that binds to -methylated DNA to stabilize DNA methyltransferases. When the function of the protein is lost, one’s genome can become unstable, and neural networks would not be properly maintained. While additional studies related to the decreased activity of these two proteins are needed, these results echo the findings of the previous study discussed, with MMC leading to more alterations in gene expression.

Even though animal models are a useful tool to study the changes in gene expression and altered epigenetic mechanisms, studies involving human patients also provide critical findings about direct modifications not only in our genome, but also in our behavior following treatment. Yang et al. were able to look at both in their longitudinal study, where they compared the difference in DNA methylation following chemotherapy to cognitive dysfunction in women who had received treatment for breast cancer10. Before starting chemotherapy, women took a performance-based cognitive function test that tested their memory, psychomotor speed, reaction time, complex attention, and ability to shift attention, all of which are symptoms of chemo brain. The same group of women were tested four more times once they began receiving treatment, until two years after they had started to receive treatment. Researchers also tested modifications in DNA methylation before treatment began and one year after starting treatment. Following one year of chemotherapy treatment, there were many significant cognitive improvements from when treatment began, including improved perception, attention, and coordination. However, memory scores never improved overtime. In regards to changes in DNA methylation, results showed that there were significant decreases in overall DNA methylation. Further analyses showed that some of these modifications were associated with the memory deficits, with 8 of the 10 largest changes seen to be in genes involved in neural functioning or signalling processes, including ECE2, a gene involved in the degradation of amyloid-beta-peptide which is linked to Alzheimer’s. These results indicate that while some symptoms of chemo brain may not be permanent, other deficits in cognitive function such as memory may be tied to altered DNA methylation patterns.

The studies discussed above are important to consider when discussing the behavioral and genetic modifications that take place when undergoing chemotherapy. Chemotherapy is one of the most widely used treatment for cancer, and there is still a long way to go in the medical field before we have potential new treatments that would replace chemotherapy entirely. It’s also one of the more effective treatment options depending on cancer type and stage, so it’s beneficial to investigate the side effects of treatment further. One of these is chemo brain, which makes patients feel foggy and may create symptoms similar to those seen in aging brains. If more is learned about these cognitive impairments, patients can receive better treatment and learn to navigate cancer with more support.

To learn more about chemotherapy and chemobrain, check out these videos from Ted-Ed and Michigan Medicine:

  1. https://ed.ted.com/lessons/how-does-chemotherapy-work-hyunsoo-joshua-no (Hyunsoo, 2019)
  2. https://youtu.be/J3oBdgGcPYQ (Michigan Medicine, 2009)

References

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  2. Hato S V., Khong A, De Vries IJM, Lesterhuis WJ (2014) Molecular pathways: The immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res 20:2831–2837.
    Hyunsoo JN (n.d.) How does chemotherapy work_ – InformedHealth. Available at: https://ed.ted.com/lessons/how-does-chemotherapy-work-hyunsoo-joshua-no [Accessed April 21, 2020].
  3. Kovalchuk A, Ilnytskyy Y, Woycicki R, Rodriguez-Juarez R, Metz GAS, Kovalchuk O (2018) Adverse effects of paternal chemotherapy exposure on the progeny brain: Intergenerational chemobrain. Oncotarget 9:10069–10082.
  4. Kovalchuk A, Rodriguez-Juarez R, Ilnytskyy Y, Byeon B, Shpyleva S, Melnyk S, Pogribny I, Kolb B, Kovalchuk O (2016) Sex-specific effects of cytotoxic chemotherapy agents cyclophosphamide and mitomycin C on gene expression, oxidative DNA damage, and epigenetic alterations in the prefrontal cortex and hippocampus – An aging connection. Aging (Albany NY) 8:697–708.
  5. Michigan M (n.d.) Coping with “chemo brain” – YouTube. Available at: https://www.youtube.com/watch?v=J3oBdgGcPYQ&feature=youtu.be [Accessed April 21, 2020].
    Sweatt DJ, Meaney MJ, Nestler EJ, Akbraian S eds. (2016) Epigenetic regulation in the Nervous System. Elsevier Inc.
  6. Wang XM, Walitt B, Saligan L, Tiwari AFY, Cheung CW, Zhang ZJ (2015) Chemobrain: A critical review and causal hypothesis of link between cytokines and epigenetic reprogramming associated with chemotherapy. Cytokine 72:86–96 Available at: http://dx.doi.org/10.1016/j.cyto.2014.12.006.
  7. WebMD (n.d.) Few Types of Cancer Treatment – by Saatvik Sharma [Infographic]. Available at: https://infograph.venngage.com/p/58124/few-types-of-cancer-treatment [Accessed February 23, 2020].
  8. WhatIsEpigenetics.com (2015) Chromatin Remodeling | What is Epigenetics? Available at: http://www.whatisepigenetics.com/chromatin-remodeling/ [Accessed April 21, 2020].
  9. Wouters J et al. (2017) Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma. BMC Med 15 Available at: https://blogs.biomedcentral.com/on-medicine/2017/06/05/comprehensive-dna-methylation-study-identifies-novel-progression-related-and-prognostic-markers-for-cutaneous-melanoma/ [Accessed April 21, 2020].
  10. Yang GS, Mi X, Jackson-Cook CK, Starkweather AR, Lynch Kelly D, Archer KJ, Zou F, Lyon DE (2019) Differential DNA methylation following chemotherapy for breast cancer is associated with lack of memory improvement at one year. Epigenetics 00:1–12 Available at: https://doi.org/10.1080/15592294.2019.1699695.