by Carlos Morales
figures by Shreya Mantri

Our cells perform extraordinary functions using information stored in their genetic material, known as DNA. Changes in DNA, known as mutations, can make cells behave erratically, which may lead to cancer. But how does cancer begin? A new model proposes that RNA — the molecular link between DNA and proteins — is at the heart of this phenomenon.

How do mutations lead to cancer?

Our DNA is packaged into 23 pairs of X-shaped units, called chromosomes, that contain instructions to make the building blocks of life: proteins. Proteins are built using information stored in DNA through a process that is mediated by RNA. As such, genetic information flows from DNA to RNA and finally to proteins. Given this sequence, mutations in DNA can change how proteins work, and consequently how cells behave. However, whether mutations are beneficial or harmful to an organism depends on their effects. 

Beneficial mutations are those that help cells perform tasks more efficiently, such as protecting people from developing heart disease, and are preferentially passed down. Over time, beneficial mutations are incorporated into a population, an idea that lies at the heart of evolution. Alternatively, harmful mutations put organisms at a disadvantage, and these mutations are less likely to be passed down. 

However, whether a mutation is beneficial or harmful isn’t always clear. There are certain mutations that are beneficial to individual cells but harmful to the organism as a whole. Furthermore, while single mutations may not be harmful, the accumulation of mutations over the lifetime of an organism can be harmful. One example for such a scenario is cancer, where mutations harmful to the organism accumulate. With enough accumulated mutations, cells become cancerous and outcompete healthy cells, leading to the death of the organism. 

One such type of mutation that has been highly researched for its role in initiating cancer is a DNA rearrangement, called a genomic translocation. Genomic translocations alter the instructions encoded in DNA and cause the creation of “Frankensteinian” fusion proteins that wreak havoc within our cells. Genomic translocations are a common cause of cancer, especially for leukemias. Our cells have a mechanism in place to protect themselves from genomic translocations that relies on DNA repair proteins to scan for and fix damage in DNA to ensure genomic translocations don’t happen. 

Genomic Translocations — cause or effect of cancer?

In 1959, David Hungerford and Peter Nowell observed that DNA in cancerous cells from patients with Chronic Myelogenous Leukemia (CML) was arranged differently than DNA in healthy human cells. Cancerous cells from CML patients had a tiny extra chromosome: the Philadelphia chromosome. In 1973, Janet Rowley made a remarkable observation — the Philadelphia chromosome was actually made by pieces of DNA from chromosomes 9 and 22 fused together (Figure 1), suggesting that the small chromosome came from a genomic translocation. 

She then found that patients diagnosed with Acute Myelogenous Leukemia (AML) had chromosomal translocations between chromosomes 8 and 21, and those diagnosed with Acute Promyelocytic Leukemia (APL) between chromosomes 15 and 17. Strikingly, patients diagnosed with any of the leukemias mentioned were unrelated, but their cancerous cells had the same translocation. This begged the question: were DNA rearrangements the result or the cause of their cancer?

Figure 1. In 1973, Janet Rowley discovered that the Philadelphia chromosome, characteristic of CML cancer patients, was made by pieces of DNA from chromosomes 9 and 22 fused together.

In CML, two genes, BCR from chromosome 9 and ABL1 from chromosome 22, break off and fuse together. The resulting fused gene is defined as chimeric, a term alluding to chimeras, the mythical creatures that were made by combining parts from different animals. Normally, ABL1 encodes a protein that tells the cell it’s ready to divide. In the fusion, the segments that turn off ABL1 are replaced with segments from BCR, and as a result ABL1 is always on. This causes undue multiplication of cells and leads to cancer. 

The silver lining is that only cancerous cells possess the chromosome fusion, so they can be targeted by treatments without harmful side effects on healthy cells. To this end, scientists have developed drugs, such as imatinib, that target the chimeric proteins in CML that the cancerous cells rely on, and in some cases have found that these treatments lead to full recovery. However, how do unrelated patients carry the same genomic translocation?

RNA-mediated Genomic Translocations

New evidence shows that RNA plays a central role in allowing genomic translocations to occur. As mentioned before, when DNA is rearranged by a genomic translocation, it creates a chimeric RNA that carries instructions for a fusion protein to be encoded. Strikingly, chimeric RNA has been identified in the absence of genomic translocations, a phenomenon that Janet Rowley and Thomas Blumenthal named the cart before the horse hypothesis. 

This discovery suggested that cancerous fusion proteins may result from a previously unknown flow of genetic information, where the RNA itself is the source of the change in the DNA. But how can RNA pass information back to DNA to cause a genomic translocation?

Pioneer work by scientists Gupta, Luo and Yen at the Baylor College of Medicine showed that introducing a specific chimeric RNA into healthy cells creates a genomic translocation that is characteristic of prostate cancer. In their model (Figure 2), RNA simultaneously binds to two regions of DNA that are in close proximity to each other, keeping them close together. Further down on the DNA, away from where the RNA is bound to, the two DNA segments bind to each other connecting the two DNA regions. Then, DNA close to this connecting structure breaks, through natural bends and twists in DNA or replication errors, where segments can then fuse together, creating a translocation.

Figure 2. The model by Gupta, Luo and Yen proposes an RNA-mediated mechanism for genomic translocations. In this model, two pieces of DNA that are physically close can be bound and held close together by a piece of chimeric RNA. If a break occurs near the bound complex, the two pieces of DNA can potentially fuse together, creating a DNA fusion that mirrors the chimeric RNA that made it possible. This model therefore suggests that an unusual flow of genetic information — from RNA to DNA – is behind some forms of cancer.

This RNA-mediated genomic translocation mechanism is key to understanding how some cancers begin. Our newfound understanding of this mechanism may help design new treatment options in the future. In the meantime, this discovery exemplifies a critical evolutionary question — why does such a risky mechanism still exist in organisms that don’t rely on it to survive?

Why keep a mechanism with harmful potential?

Although RNA-mediated genomic translocations appear to precede cancer, it turns out that there are organisms that rely on this process. Single-cell organisms, such as ciliates, use RNA to re-assemble their genomes. The same mechanism is observed in other eukaryotes, such as yeast, which implies that an ancient biochemical process has been preserved over evolutionary time. One possible explanation behind this is that this mechanism grants a critical advantage — adaptability.

Benefits that outweigh the costs 

Species must adapt to their environments to survive. Environments are ever-changing and as such, are mostly dynamic rather than stable. This pushes species to constantly evolve to keep up with changes happening in their environments (Figure 3).

Figure 3. Faithful genomic reproduction is key in stable environments, so that evolutionarily-selected mechanisms are faithfully carried out. However, in dynamic environments, diversity in phenotypes can be more beneficial for the population, so dynamic genomes that can accumulate potentially-beneficial mutations are favored. The RNA-mediated genomic translocation mechanism described in this article might be one mechanism introducing dynamic malleability to our genomes.

One way they do so is by accumulating beneficial mutations. Over time, these mutations change instructions in DNA, which may translate into species taking on new roles in their environment. However, since mutations can also bring negative consequences, introducing them arbitrarily without caution would cause more harm than good. That is why having DNA repair mechanisms is important. In RNA-guided genomic translocations, RNA molecules themselves direct where mutations happen in DNA, potentially contributing to evolution, as seen in ciliates. Perhaps this mechanism has been maintained in humans for evolutionary advantages, but the exact reason is as yet unknown. 

In the context of cancer, understanding the mechanism behind RNA-mediated genomic translocations has the potential to reveal new areas of study in oncogenesis (the origin of cancer) that may extend to new preventive care applications. Like how Gupta and colleagues identified an RNA as the cause of a known genomic translocation in prostate cancer, other RNAs may be identified as the cause of cancers of unknown origin. 

Carlos Morales is a first year PhD student at the Systems, Synthetic and Quantitative Biology program at Harvard Medical School. You can find him on Twitter @solracTV and on LinkedIn.

Shreya Mantri is a PhD student in Biological and Biomedical Sciences at Harvard Medical School.

Cover image by scidartacademy on pixabay.

For more information:

  • Watch this video, which illustrates how genomic translocations occur.
  • Check out this article by Sachin Kumar Gupta and Laising Yen that determines the requirements for a successful translocation event as per their model described above.

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