Chromosomal instability study yields possible cancer treatment approach

In cancer, there are often large-scale deletions, rearrangements or other disruptions to our genetic information, which lead to a phenomenon known as chromosomal instability. This process has long been recognized, but new discoveries are helping us to better understand its role in cancer development.

A recent study from MD Anderson researcher George Calin, M.D., Ph.D., has discovered a culprit responsible for chromosomal instability in many cancers, which could provide new targets for developing cancer therapies. Calin spoke with us about the study.

What is chromosomal instability?

Chromosomes are the homes of our genes, which are the sequences of DNA that code for proteins in our cells. This is the central dogma of molecular biology.

Chromosomal instability occurs when the chromosomes, which contain many genes, become broken by different mechanisms. For example, the end of a chromosome could break and join with a different chromosome, or sections from the middle of a chromosome could become broken and go missing.

There are many ways that chromosomal instability can occur, but these changes in our chromosomes are a hallmark of cancer. It’s associated with a bad prognosis.

Why are you interested in studying chromosomal instability as it relates to cancer?

The first research to show that chromosomes were abnormal in cancer was published in the late 19^th and early 20^th centuries — over 120 years ago. In that time, the scientific community has not been able to identify a clear explanation of why chromosomal instability occurs. Is chromosomal instability a cause of cancer, or a consequence of cancer?

Many researchers have shown that chromosome instability is associated with metastasis and resistance to many types of therapy, including chemotherapy, radiation and even immunotherapy — specifically immune checkpoint inhibitors. So we understand that chromosomal instability is associated with all of these phenomena, but we need to understand if it is causing them.

This is an extremely important question. If we were to discover that this instability is a cause of cancer, we could then target that process to treat the cancer and deliver better care to our patients.

This study focused on the role of CCAT2 in chromosomal instability. Could you explain what that is and why you’re interested in it?

Years ago, we discovered a new kind of gene that does not code for a protein, but instead creates what we call a non-coding RNA (ncRNA). CCAT2, which stands for colon cancer associated transcript 2, is a long ncRNA, which consists of about 2,000 nucleotides. My lab was the first to study and identify this gene and its connection to cancer.

We focused on CCAT2 because it’s located on chromosome 8 in a region that is often amplified in cancer cells, meaning there are excess copies of this chromosome. It also harbors other genes, such as the MYC oncogene, that we know is responsible for driving cancer development.

We found that when CCAT2 is overexpressed, meaning it is present at very high levels, we see chromosomal instability. We saw this in every type of cancer we analyzed. We found this very interesting and decided to study it further.

What are some of the key findings in your study?

We focused this study on colorectal cancers through a collaboration with Scott Kopetz, M.D., Ph.D.; stomach cancers through a collaboration with Jaffer Ajani, M.D., and peritoneal carcinomatosis, which is a deadly complication that can occur when gastrointestinal cancers spread all over the belly. We showed that these cancers:

• have very high levels of CCAT2 expression,
• are more metastatic and
• do not respond as well to standard chemotherapy.

We also found the patients with these cancers and high CCAT2 tend to have worse outcomes. There is clearly a need to provide better options for these patients.

Our study is important because it was the first to prove that high levels of CCAT2 can cause chromosomal instability in vitro, meaning in cancer cells grown in the laboratory. We also showed this in a genetically engineered mouse model with high CCAT2 levels.

We analyzed colon organoids, a simplified version of the colon we grow in the laboratory, from normal mice and mice with high CCAT2 levels. Those from the CCAT2 mice had significantly more chromosomal instability, and this occurred before the cells became cancerous. This means that very likely CCAT2 is the cause of the instability.

We also discovered a new mechanism which we can target by therapeutics. We found that CCAT2 binds directly to a protein named BOP1, which is important in regulating how proteins are produced from genes. BOP1 affects the way chromosomes move through the cell nucleus too. When CCAT2 binds to BOP1, the normal movement of the chromosomes is disrupted. Finally, we found that BOP1 and CCAT2 together activate another gene, Aurora Kinase B, which is known to drive cancer development and is the target of many new therapies.

This is a very complex process that provides important insights into our understanding of what drives chromosomal instability and cancer.

How might this chromosomal instability research benefit cancer patients?

There are two benefits for patients: useful biomarkers and future therapies.

We imagine that we could take a liquid biopsy, or a blood sample, and analyze the levels of CCAT2 in a patient. If it’s highly expressed, then we may predict that certain therapies are less likely to be effective and we should look into alternate regimens.

For future therapies, we are working on developing agents to target these long ncRNAs in MD Anderson’s Non-Coding RNA Center, which I lead with Anil Sood, M.D. We envision that we could develop a chemical or small piece of RNA that binds to and blocks CCAT2 activity. Because CCAT2 causes chromosomal instability early, before cancer develops, this type of intervention could be useful in treating very early-stage tumors. By preventing chromosomal instability, we may allow other therapies to be used more effectively.

For a full list of collaborating authors, research support and disclosures, please read the full paper here.

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