In our previous blog posts, we explored the complex interplay between genetics and the environment in shaping human traits and diseases. We looked into the challenges of the human genome project and the importance of considering both genetic and environmental factors when looking at health in general.
In this blog (3), let's delve deeper into the world of genetic testing for cancer risk (premise is the same when assesing pretty much any disease). Genetic testing can provide valuable information about an individual's susceptibility to certain types of cancer. However, it's essential to understand the limitations and implications of genetic testing before making decisions about your health.
In this blog post, we will explore:
Types of genetic testing for cancer risk (germline vs. somatic, monogenic vs. polygenic)
Benefits and limitations of genetic testing
Factors to consider before getting genetic testing
The role of genetic testing in cancer prevention and management
By the end of this blog post, you will have a better understanding of the role of genetic testing in cancer risk assessment and the importance of a comprehensive approach to cancer prevention and management.
Germline vs. Somatic Mutations
Germline Mutations: These mutations are inherited from a parent and are present in all cells of the body. They can increase an individual's risk of developing certain types of cancer.
Somatic Mutations: These mutations occur in individual cells during a person's lifetime and are not passed on to offspring. While somatic mutations can contribute to cancer development, they are not typically inherited.
Image Credit: Medium/@SbarnettARK
Monogenic vs. Polygenic
Monogenic: These cancers are caused by a single gene mutation. Examples include BRCA1/BRCA2 - associated breast and ovarian cancer, and Lynch syndrome.
Polygenic: These cancers are caused by a combination of multiple genetic factors, often interacting with environmental factors. Most common cancers, such as breast, colon, and prostate cancer, are polygenic.
Percentage of Cancers Attributed to Germline/Monogenic vs. Somatic
Germline/Monogenic: While monogenic cancers can be highly penetrant, they account for a relatively small percentage of overall cancer cases. Estimates suggest that germline mutations contribute to around 5-10% of cancers [1]
Somatic: The majority of cancers are attributed to somatic mutations, which can arise from a variety of factors, including genetic predisposition, environmental exposures, and lifestyle choices.
Beyond Genetic Mutations
The traditional view of cancer has focused on genetic mutations as the primary drivers of tumorigenesis. However, emerging evidence suggests that metabolic dysregulation also plays a crucial role in cancer development. There is ample evidence [2] supporting the metabolic theory of cancer and showcasing how genetic mutations, epigenetic changes, and environmental factors can contribute to this complex disease.
Oncogenic Driver Genes in Healthy Cells
Conditional Activation: Oncogenic driver genes, when activated under certain conditions, can promote cancer development. These genes may be present in healthy cells but become dysregulated in cancer cells due to various factors, including metabolic alterations.
Environmental Factors: Exposure to environmental carcinogens can activate oncogenic driver genes and disrupt cellular metabolism, leading to cancer.
Mitochondrial Transplantation Studies
Cybrid Experiments: Cybrids, which are cells created by fusing enucleated (nucleus-removed) cancer cells with healthy cells, have been used to study the role of mitochondria in cancer. These experiments [3] have shown that transplanting mitochondria from cancerous cells into healthy cells can induce metabolic reprogramming and promote tumorigenesis.
Metabolic Reprogramming: Mitochondrial dysfunction in cancer cells can lead to metabolic reprogramming, such as increased glucose uptake and decreased oxidative phosphorylation. Transplanting these dysfunctional mitochondria into healthy cells can induce similar metabolic changes, suggesting that mitochondrial dysfunction is a key driver of cancer.
Oncogenic Signaling: Mitochondrial dysfunction can also activate oncogenic signaling pathways, promoting cell growth and proliferation.
Image Credit: Physionic
The Limits of Genetic Scores
The Human Genome Project unveiled a wealth of information about our genetic makeup. One exciting prospect was the polygenic risk scores (PRS) to predict an individual's susceptibility to various diseases. However, a recent study [4] by UCL researchers throws cold water on this idea, suggesting that PRS may not be as useful as initially hoped.
What is Polygenic Risk Scores (PRS)?
PRS combine information from an individual's DNA, analyzing thousands or even millions of genetic variations. These variations might not be strong enough to cause disease on their own, but when considered together, they can create a score indicating a potential risk.
The Limitations of PRS
The UCL study, which looked at 926 polygenic risk scores for 310 diseases, found that PRS performed poorly in predicting common diseases. While PRS may work in research settings, they may not be reliable or practical for individual risk assessment in a clinical setting.
Here are some key limitations of PRS:
Low Predictive Power: PRS often explain only a small portion of the overall disease risk. Environmental and lifestyle factors play a significant role, which PRS currently doesn't capture effectively.
Specificity Challenges: PRS may not be specific enough to predict a particular disease. A high score might indicate a risk for multiple diseases, making it difficult to determine the most likely culprit.
Key Findings:
Low Detection Rates: For breast cancer and coronary artery disease, PRS identified only 10% and 12% of eventual cases, respectively.
High False Positive Rates: To capture 10% of cases, the researchers had to set a low threshold, resulting in a high false positive rate of 5%. This means that 5% of individuals without the disease would incorrectly test positive.
“Our results build on evidence that indicates that polygenic risk scores do not have a role in public health screening programmes.”
Shifting Focus: From Germline to Somatic Mutations
These findings highlight the limitations of using PRS for individual risk assessment. While germline mutations (inherited genetic variations) can contribute to disease risk, the majority of cancers are attributed to somatic mutations, which occur during a person's lifetime.
The Role of Lifestyle and Environment
Numerous environmental factors have been linked to increased cancer risk, including:
Lifestyle Factors: Smoking, excessive alcohol consumption, unhealthy diet, obesity, stress, and lack of physical activity are all associated with increased cancer risk.
Environmental Exposures: Exposure to carcinogens, such as asbestos, radiation, and certain chemicals, can increase the risk of cancer.
Infectious Agents: Some viruses and bacteria can contribute to cancer development.
The Complex Interaction
The interplay between genetic and environmental factors in cancer development is complex and often difficult to disentangle. While genetics can create a predisposition, environmental factors can trigger or modify the expression of cancer-related genes.
Image Credit: PMID: 18626751
The Impact of Genetic Predisposition
While genetic factors can influence cancer risk, it's important to recognize that most cancers are polygenic, meaning they are influenced by multiple genes. Additionally, environmental factors play a crucial role in disease development.
A study by Hemminki et al. (2000) analyzed cancer risk in monozygotic and dizygotic twins [5]. They found that:
Environmental factors: Non-shared random environmental effects were the largest factor for all cancers, accounting for 58-82% of the total variation.
Genetic factors: Heritability estimates were statistically significant for cancers of the colorectum (35%), breast (27%), and prostate (42%). However, these estimates were lower than the environmental effects.
It is estimated that only 1 percent of cancers are caused by “cancer syndromes” and up to 5 percent result from highly penetrant single-gene mutations; thus, the majority are polygenic.
A Swedish family cancer database, containing 10 million people, is the largest population-based data set ever used for studies on familial cancer, said Hemminki. The database has been used in modeling cancer causation and has revealed that environmental causes explained most of the total variation for all neoplasms except thyroid cancer, for which heritable causes were largest.
Implications for Clinical Use
These findings suggest that PRS may not be reliable or practical for individual risk assessment in a clinical setting. The low detection rates and high false positive rates could lead to unnecessary anxiety and medical interventions.
While PRS offer insights into genetic risk, they are not a panacea for predicting disease. A more comprehensive approach that considers both genetic and environmental factors is essential for understanding disease risk and developing effective prevention strategies.
The Importance of Family History and Screening
While PRS may have limitations, a strong family history of cancer remains a crucial risk factor. If you have a family history of a particular type of cancer, it's essential to discuss it with your healthcare provider. They may recommend genetic testing or increased screening to assess your individual risk.
It's important to note that while genetic testing can identify individuals at increased risk for certain cancers, it cannot predict with certainty whether someone will develop the disease. A combination of genetic, environmental, and lifestyle factors likely contributes to cancer risk.
Potential Downsides of Genetic Testing
Genetic testing can have both benefits and drawbacks. Some potential downsides include:
Psychological Stress: Learning about a genetic risk can cause anxiety and distress, especially if it increases the risk for oneself or loved ones.
Uncertainty and Stress: Variants of uncertain significance (VUS) can lead to uncertainty and anxiety.
Cost: Genetic testing can be expensive, especially if not covered by insurance.
Follow-up and Prevention: Positive test results may require additional medical follow-up and potentially costly preventive measures.
Privacy and Discrimination: Concerns about privacy and discrimination based on genetic information.
False Results: Given the high false-positive or false-negative results can lead to unnecessary anxiety or a false sense of security.
Misinterpretation of Results: Individuals may misinterpret genetic test results, leading to incorrect decisions about their health and lifestyle.
Fatalism: Learning about a genetic predisposition can sometimes lead to a sense of fatalism, believing that one's fate is predetermined. This can lead to feelings of hopelessness and decreased motivation to adopt healthy behaviors.
Overreaction: In some cases, individuals may take drastic measures based on genetic test results, such as undergoing unnecessary surgeries or treatments.
Conclusion
Genetic risk scores are a developing technology with potential limitations. While they can provide some insights, a comprehensive approach to disease prevention and management should consider both genetic and environmental factors.
It's essential to maintain open communication with your healthcare provider, discuss your family history, and adopt healthy lifestyle habits to reduce your overall risk of disease.
Remember: Early detection and prevention are key to improving outcomes for many types of cancer.
Don't hesitate to seek medical advice if you have any concerns about your health.
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