Dr. Tom Caskey is an internal medicine doctor with a long research career in genetics and biomedical research. His 50+ years of research have focused on the genetic basis of human diseases. Among his contributions are helping to develop PCR technology for clinical and forensic applications and discovering the universality of the genetic code. His genetic research identified the genetic basis of 25 major inheritable diseases. Dr. Caskey’s current research focuses on the application of the whole genome sequence and metabolomics of individuals toward the objective of disease risk and its prevention.
Why is genetic testing important for addressing cancer?
First and foremost, all cancer is genetic. Cancer occurs because of mutations in certain genes that result in a cell being able to replicate without constraints. There are two ways in which cancer occurs. One way is that the risk for cancer is inherited, and several types of cancer can run in families. The second mechanism is one by which a new “spontaneous” mutation occurs in the DNA in the cells of an individual. Those new mutations have to be in specific genes, either driver genes that can make a cell replicate rapidly or slow-down genes which become non-functional from the mutation.
How does whole genome sequencing (WGS) differ from whole exome sequencing (WES) or genotyping?
Whole genome sequencing provides a clearer and more comprehensive picture than that provided by the targeted technologies.
Whole exome sequencing (WES) only sequences exons, the parts of genes that code for amino acids, the building blocks of the proteins used by our bodies. Where whole exome sequencing can provide sequence data on just 2-3% of the total DNA, whole genome sequencing produces sequence data for all of the DNA. This means that the mutations occurring outside of the exons that can cause cancer would be missed by WES but could be identified via WGS.
Genotyping also serves a purpose, but it is very focused and quite limited compared to whole genome sequencing. WGS looks at the entire DNA sequence whereas genotyping only looks at specific areas. Say you’ve lost your wallet in a football stadium. Genotyping is comparable to taking a flashlight and looking for your wallet in just a couple of spots. Whole genome sequencing turns on all the floodlights, illuminating the entire stadium so that you can search around every seat.
How is genomics used to assess inherited cancer risk?
With an inherited risk for cancer, it’s important to remember that you don’t inherit cancer itself, you inherit the risk of developing cancer. This was first made clear by Alfred Knudson’s studies of retinoblastoma. He won the Nobel Prize for making this discovery. He proposed the “two-hit hypothesis” in which you can inherit a mutation that conveys the inherited risk, but to develop cancer, you must also have a mutation arise in a cell during your lifetime, resulting in another error in your DNA within that cell that leads to the growth or start of the cancer. With Human Longevity, we perform whole genome sequencing, which with a single test, allows us to look for any inherited variations in your DNA that impart inherited risk of all of the known types of heritable cancer.
What is very important to understand is that DNA sequencing can only identify a risk gene. This is not a cancer diagnosis in an individual, because that takes the second event. For example, 40% of individuals who have inherited a risk for breast cancer will never get cancer..
Another important thing to understand is the impact beyond the individual. If you have inherited the risk of a certain cancer, but you’ve never had it, your children have a 50% chance of inheriting that risk also. Therefore, the identification of a gene associated with cancer risk in an individual opens up the opportunity to prevent cancer by early diagnosis in that entire family. Anyone who has an inherited risk has a high chance of developing cancer whether or not their parent did. Therefore, when a cancer risk variant is identified in an individual, all related family members need to be tested to find out which individuals also have substantial cancer risk.
What types of cancer are known to run in families?
The ones that have been in the news a lot include breast cancer, colon cancer, kidney cancer, and prostate cancer. However, there are probably 130 to 140 cancer types for which risk can be inherited.
Are there certain populations that need to be more concerned about inherited cancer risk?
Yes, certain ethnic populations can have a higher risk of predisposition to cancers because those genes are more common in the population. For example, Southeast Asians tend to have a higher risk of liver disease and stomach cancer, while individuals with central European Jewish heritage have a higher risk of breast and ovarian cancer. Moreover, nearby Arabic populations also have a high frequency of breast and ovarian cancer.
What about the second category of cancers that are not known to have an inherited risk component?
These cancers do not require an inherited risk and can occur from single mutation events. In fact, these are currently the majority of cancers seen in clinics. New mutations create what we call driver genes, where a single mutation can lead to rapid replication in the cell, resulting in cancer. A classic example is leukemia. All types of leukemia, both childhood and adult, are due to new mutations arising in the individual.
Dealing with these cancers requires using a variety of strategies other than genome sequencing. Early detection of cancer is critical to getting cured efficiently, as once cancer has spread to other organs, it is much more difficult to cure. However, if you identify the early lesions of cancer then it can be surgically removed. Whole-body MRI scanning, which is discussed at length elsewhere in this publication, can be used to detect and locate cancerous lesions. In particular, whole-body imaging through the 100+ longevity program has had great success in the identification of prostate cancer. Furthermore, biomarkers, typically molecules that can be detected in the serum from a blood sample, may indicate the presence of cancerous cells. One example is CA-125 which is often used as a screening test for ovarian and uterine cancers.
A third method of detection also discussed in this publication is liquid biopsy, one example of which are the tests for detecting colon cancer. While, forty percent of colon cancers can be identified through inherited cancer risk, the remainder are not, but may be detected using liquid biopsy. These tests look for abnormal cells that are shed and therefore can be identified by DNA sequencing as cancer cells. A positive result would lead to a follow-up procedure such as a colonoscopy to confirm the result.
Early detection of cancer requires the integration of hi-tech diagnostics, where the data from every test are evaluated by experts and integrated to form a complete picture of an individual’s health status. With 100+, we use this multi-prong approach that integrates genomics data, whole-body MRI, blood biomarkers, and liquid biopsy where appropriate.