Empower Our Patients – Increase Their Survival.
Empower their Community and Workplaces – Exponentially Increase Survival

“We work to ensure that today’s research and knowledge are fully utilised and integrated into today’s patient toolkit. By simplifying both the science and the knowledge into a format that patients and caregivers can understand and effectively apply, we help achieve this” ~ Steve Holmes 

Introduction:

Imagine that every cell in your body is like a bustling city with lots of important jobs to do. In this city, one of the most important teams is the Repair Team, and two of the most skilled workers on this team are BRCA1 and BRCA2. They work alongside another important team member, BAP1, who helps regulate the city’s growth. Their job is to fix the city’s blueprint—the DNA—whenever it gets damaged and to keep the cell city running smoothly. Cholangiocarcinoma is known as a more aggressive cancer, and these repair workers sometimes struggle to keep up, leading to big problems in the city. Let’s explore their story together and learn how we can help keep our cell cities safe.

1. Meet the Repair Team: BRCA1, BRCA2, and BAP1

Who They Are: BRCA1 and BRCA2 are like superhero genes that live in the nucleus (City Hall) of our cell city. They’re responsible for fixing any problems in the city’s blueprint (the DNA) to keep everything running smoothly. These genes instruct the city planners (mRNA) on how to fix and maintain the city. BAP1 is another key player that also resides in the nucleus, acting like a conductor in an orchestra. Instead of directly fixing the blueprint, BAP1 ensures that all the different parts of the cell are working together in harmony, controlling the pace of cell growth and making sure that damaged DNA is properly repaired. BAP1 helps maintain a healthy environment in the cell city, preventing uncontrolled growth that could lead to problems like tumors. In cholangiocarcinoma, these superhero genes are especially important because the bile ducts are critical pathways that need to stay clear and functioning well.

What They Do: DNA is like a giant instruction manual that contains all the genes, which act as specific instructions for each cell city. The nucleus (City Hall) houses this manual, ensuring that the right grouping or sequence of genes is available to guide the town planners (mRNA) on what to do and when. This way, the cell city can perform its job and stay healthy.

2. When Things Go Wrong: The Tools Break in Cholangiocarcinoma

Broken Tools: Sometimes, BRCA1, BRCA2, or BAP1 can’t do their jobs properly because their tools are broken. In cholangiocarcinoma, this can happen when mutations (mistakes) occur in these genes. Imagine if a superhero’s gadgets stopped working—suddenly, they can’t fix things as well as they used to. When BRCA1 or BRCA2 are mutated, their ability to repair the DNA blueprint is compromised. When BAP1 is mutated, it can’t maintain the right environment for healthy cell growth, leading to problems in the city.

Unrepaired Damage: Without BRCA1 and BRCA2 fixing the DNA replication problems, and without BAP1 properly managing growth and the cell environment, the bile duct cells get more and more damaged and go rogue. Over time, this damage spreads to other cells, and soon there are clusters of rogue cells growing out of control, multiplying rapidly, and forming tumors in the bile ducts, which can block the flow of bile and cause serious health issues.

3. What Happens Next: Cholangiocarcinoma Takes Hold

City Under Attack:

Imagine that the bile in the bile duct becomes too toxic—like a corrosive liquid that’s much stronger than usual. As this toxic bile flows through the bile ducts, it starts to burn and damage the cells it touches. Normally, the cells in the bile ducts are strong enough to handle bile, but this time, the bile is so toxic that it causes varying degrees of injury to different cells.

Some cells are hit harder than others, with the toxic bile burning through their outer walls and reaching City Hall (the nucleus) where the blueprint (DNA) is stored. When the bile burns through, it can cause serious damage, injuring many important genes, including the superhero genes BRCA1 and BRCA2, which are responsible for repairing damage. Cells with damaged BRCA genes lose their ability to repair DNA and control their growth properly, while other, less damaged cells might continue to function more normally.

Cell Cities Out of Control:

In the cells where BRCA genes are damaged, the repair crew can’t do their job correctly, leading to faulty instructions within those cells. As these cells replicate, they copy the DNA mistakes over and over, which leads to more errors accumulating with each generation. These mistakes cause the cells to grow and divide in an uncontrolled and disorganized way, forming clusters of chaotic, rapidly multiplying cells.

Other less damaged cells, although not growing as rapidly, may still get caught up in this process, adhering to the rapidly growing rogue cells and becoming part of the cluster. Together, these cells form a mass that grows larger and larger.

That’s why we often see tumors with a mix of different genes that have mutated within the same tumor. Some genes, like BRCA, have more damaging consequences when they’re mutated, leading to more aggressive and uncontrollable growth, while other mutations may contribute in different ways to the overall behavior of the tumor.

4. Fixing the Problem: Calling for Backup in Cholangiocarcinoma

Calling in New Helpers:

Even if BRCA1, BRCA2, and BAP1 can’t do their jobs because their tools are broken, doctors have special medicines that can help. One such treatment in cholangiocarcinoma is called a PARP inhibitor. PARP inhibitors, like Olaparib (Lynparza) and Rucaparib (Rubraca), are specialized tools that block a different repair pathway in the cell. When this pathway is blocked, the defective cells struggle to survive, which helps stop the out-of-control cell growth and makes it harder for tumors to form and grow. These medicines act like reinforcements, targeting the defective cells directly and preventing them from causing further chaos in the cell city.

Targeted Therapy:

Another approach is targeted therapy, which is designed to specifically attack cancer cells that have certain mutations, like those in BRCA1, BRCA2, or BAP1. These therapies are like specialized teams that zero in on the rogue cells, helping to keep the cell city safe even when the main repair crew can’t do its job.

For example, Pembrolizumab (Keytruda), an immunotherapy drug, is sometimes used in tumors with specific genetic features, including those seen in some cholangiocarcinomas with BAP1 mutations. Erlotinib (Tarceva) has also been used in some bile duct cancers based on the specific genetic makeup of the tumor.

These targeted therapies represent a more personalized approach to treating cholangiocarcinoma, offering options that specifically address the unique genetic changes in each patient’s cancer cells.

5. Understanding the Mutation

By now, you may already know whether your BRCA1, BRCA2, or BAP1 mutations are inherited or developed later in life. Inherited mutations are passed down from your parents and are not within your control. However, it’s crucial to understand that having an inherited BRCA mutation doesn’t mean cancer is inevitable. These mutations only become a significant risk factor if the cells experience injury or damage that the mutated gene cannot effectively repair. This means that even an inherited mutation still requires a somatic trigger to potentially lead to cancer.

Somatic mutations, which develop after birth, typically arise from chronic injury to cells, often influenced by factors like aging, lifestyle choices, and, in some cases, environmental exposures. However, somatic mutations can also result from sudden injuries, such as physical trauma. For instance, if the liver is injured in a car crash or other severe accident, the resulting damage could potentially alter bile composition over time in ways that go undetected, creating conditions that might lead to somatic mutations and damage to the bile ducts—thus becoming a silent killer. But this is purely an example to provide scope. While such injuries are less commonly associated with bile duct cancer compared to chronic exposure to toxic bile, they are still important to consider.

Understanding that both chronic and acute injuries can contribute to somatic mutations provides a more complete picture of how these mutations might arise. This insight can help patients who are searching for answers about their own medical history and potential triggers. By focusing on reducing harmful lifestyle factors and minimizing exposure to environmental risks, patients can take proactive steps to manage their health, even in the face of complex and challenging conditions like cholangiocarcinoma.