Cancer & Genetics
A family history of cancer is scary. Our genetic counselors help families understand their risks.
Some people have a higher risk for cancer due to inherited genetic mutations. Recognizing this risk can allow for earlier detection and even prevention of some cancers. Are you concerned about cancer in your family?
Genetic counseling and testing can help you determine if you or others in your family may have an inherited genetic risk for cancer and help guide you through the process of screening and medical management for individuals at higher risk.
Understanding Hereditary Cancer & Genetic Testing
Cancer is unfortunately very common, affecting approximately 1 in 2 men and 1 in 3 women during their lifetime. Although most cancers are not inherited, some families do have a higher risk for cancer than others. Genetic counseling and testing can help determine if there may be an inherited genetic risk for cancer in your family and who in your family is at higher risk for cancer. It can also help guide the appropriate screening and medical management for individuals at higher risk.
Here we discuss the connection between genes and cancer, provides an overview of the genetic testing process, and touches on some important considerations when deciding whether or not to pursue cancer genetic testing.
Research over the past few decades has shown that genes play a key role in the development and behavior of cancers. In short, genes are the instructions that tell our cells how to grow and function to keep us healthy. Therefore, changes within those instructions can cause cells to lose their regulation and grow out of control, leading to a tumor.
The majority of cancers are sporadic, or occur just by chance. Within cancer cells, genetic mutations are found that are different from the healthy, non-cancerous cells in the body. As noted above, these genetic mutations are understood to cause and influence the abnormal growth of the cancer cells. Typically, sporadic cancers occur in people when they are older, and there is not a strong pattern of cancer within the family (although because cancer is common, it is not unusual to have some history of cancer in the family). The causes for sporadic cancers are largely unknown, but may include environmental and lifestyle risk factors (e.g. smoking, UV exposure) as well as the natural and unavoidable process of aging.
In about 5-15% of cancers, the underlying cause is due to an inherited gene mutation that increases the risk to develop certain types of cancer during the lifetime. An inherited mutation (passed from parent to child) is present from conception and is found in every cell of the body. Although by itself the mutation is not cancerous, it increases the chance for other random mutations to occur and accumulate in the cells, leading to the development of cancer.
Here are some things that may indicate that someone has a higher risk for hereditary cancer:
- early-onset cancers (i.e. diagnosed before the age of 50 years),
- individuals with multiple primary cancers (i.e. 2 or more cancers of separate origin, not the spread of one cancer to other areas of the body)
- rare types of cancer (i.e. ovarian)
- family history of the same type or related types of cancers in multiple individuals and generations
- persons from certain ancestral backgrounds (e.g. Ashkenazi Jewish ancestry) have a higher chance to carry mutations common to those populations
- a known pathogenic variant in a cancer risk gene has been previously identified in a relative
A third category for classifying cancer risk is familial cancer. These descriptions may be used when there appears to be more cancer in a family than we would expect by chance alone, but the cause is not identified. There may be a combination of multiple genetic and/or environmental risk factors that are increasing the risk for cancer in the family, or there could be a genetic cause for the cancer that has not yet been identified. Therefore, until more clear answers can be found, the most important message is that the family should be considered at some level of increased cancer risk, and be managed based on their unique history.
Genetic testing for hereditary cancer first starts with a genetic consultation to collect and analyze the personal and/or family history of cancer. If a pattern suggestive of hereditary cancer is identified, then genetic testing may be considered for further clarification or confirmation of the specific cancer risks.
Depending on the history, it may be recommended that a specific individual in the family is the first to undergo the genetic testing. Whenever possible, it is recommended to initiate testing in a family member who has had a diagnosis of cancer most suggestive of hereditary causes, since this is the most likely person to have a mutation identified through the testing. However, we understand that this is not always possible, such as when the family member is deceased or is otherwise unable or unwilling to undergo the testing.
If a cancer-associated gene mutation has previously been identified in the family, then testing can be targeted to that specific mutation with the ability to definitively confirm or rule out increased risk. If no prior testing has been done, then genetic testing may include one or a few specific genes that are strongly suspected based on the history. Alternatively, in some cases, more broad panels to include testing of multiple genes may be considered.
To help understand the possible results, it is important to have a brief background about what genetic testing looks for. Each of our genes is made up of a string of thousands of letters. These letters make up an instruction manual for how to build a protein, and the proteins are what is actually making our body function how it should. Genetic testing generally looks at genes through sequencing and deletion/duplication analysis. Most of the genes that we associate with hereditary cancer risk make proteins that help our bodies prevent various types of cancer from forming.
My Results are Positive - What does that mean?
A positive result (may also be called ‘mutation detected’) confirms inherited risk for cancer in the person who was tested. A mutation means that the lab found either a spelling error (by sequencing), or missing or extra letters (by deletion/duplication studies) that we know make the instructions for that gene incorrect. If the instructions are incorrect, then that gene will either not produce a protein, or will produce a protein that doesn’t do what it is supposed to. In the case of hereditary cancer genes, if they are not producing a protein, or are producing a protein that doesn’t function properly, these non-working genes can cause an increased risk for related types of cancer.
Each gene is related to different types of cancer. Therefore, if someone has a mutation in a gene related to hereditary cancer, identifying which gene the mutation is in can tell us what forms of cancer someone may be at risk for, and how high that risk is. Once we know that someone is at an increased genetic risk for cancer, appropriate high-risk screening and management options should be discussed.
Finding out that someone carries a gene mutation associated with an increased risk for hereditary cancer means that their relatives may also be at an increased risk. Most of these genes are passed down in an autosomal dominant pattern, meaning that if someone carries a gene mutation, there is a 50% risk for first-degree relatives (parents, siblings, and children) to also carry it. If we have an identified familial gene mutation, then we can use that information to offer testing to family members to determine who may also have a higher hereditary risk for cancer. If relatives are also found to carry this gene mutation, then recommendations can be made for high-risk screening and management. If relatives are found to not carry the gene mutation, then we can reassure them that they should have a risk for cancer that is similar to those in the general population.
My Results are Negative - What does that mean?
There are actually two different type of negative test results when it comes to hereditary cancer genetic testing: a true negative and an uninformative negative.
An uninformative negative rules out all mutations detectable by the particular test performed. The lab screens for mutations by looking for harmful spelling errors in the gene (by sequencing) or missing or extra letters (by deletion/duplication studies). An uninformative negative means that the lab looked through all of the letters in the gene(s) that were tested and did not find any mutations (harmful spelling errors or missing/extra letters). An uninformative negative genetic test result means that the chance for a strongly genetic cause for the cancer in your family is likely low but not zero.
With an uninformative negative genetic test result, it is important to interpret that result in the context of the family history. It is possible that a gene mutation is responsible for a family history of cancer, but it was just not passed down to the individual that was tested. It is also possible that there could be a mutation in the genes that were examine that cannot be found by our current technology. New genes related to an increased hereditary cancer risk are continually being discovered, so there is the potential that there could be a gene that is increasing the risk in a family that we just have not found yet.
Because of all of this, even if someone has an uninformative negative genetic test, if they have a strong family history of cancer they still may have an increased risk. If genetic testing is negative, we determine someone’s risk as well as screening and management guidelines based on their family history.
If there is already a known mutation in the family and testing does not identify that mutation, this is considered a true negative result, which rules out the increased cancer risks associated with that known mutation. Unless other, unrelated risk factors are identified in the history, screening and management recommendations are based on general population guidelines. Further, any children of an individual with a true negative result are not at risk to inherit the mutation and testing for them is not necessary (unless they have a suspicious history of cancer on the other side of their family).
My Results Say I Have a Variant of Uncertain Significance - What does that mean?
A variant of uncertain significance (VUS) is when the lab found a spelling change (by sequencing) or a missing or extra piece (by deletion/duplication studies), but are not entirely sure what it means.
Most of the time, researchers get more information about the VUS and find that it is not linked with an increased risk for cancer. The majority of VUS findings are spelling errors or extra/missing pieces in the gene that don’t change the instructions, and thus do not affect the protein that the gene makes.
An example would be the sentence A CAT RAN. A VUS would be similar to if the sentence said A CAT RUN instead of A CAT RAN. The spelling error that changes RAN to RUN makes the sentence not make grammatical sense, but it doesn’t change the overall meaning of the sentence.
In some cases, research studies can be offered to family members to help determine whether the spelling error or missing/extra piece is harmful or not, but it can take months to years to reach more definitive answers. Due to the uncertainty of a VUS result, testing of other family members for the variant is not usually recommended outside of research studies. Until the result can be clearly interpreted as a positive or negative, cancer risk and screening would be based on the individual and/or family history of cancer.
There are several reasons why someone may consider genetic testing for hereditary cancer predisposition, which are outlined below.
High-Risk Screening and Risk Management
One of the primary benefits of knowing about hereditary cancer risk is the ability to take control of that risk in partnership with your healthcare team. Genetic testing and clarification of hereditary risk for cancer helps to guide recommendations and decisions for appropriate medical management, cancer screening, and cancer prevention approaches. High-risk cancer screening may include earlier and/or more frequent screenings to try to detect cancer at the earliest, most treatable stages. Surgery or medications may also be available to reduce the overall risk of developing cancer. Specific recommendations should be discussed with your providers.
Potential to Rule Out Increased Risk
If the cancers in a family are caused by a known mutation, and testing rules out that mutation in a family member (a true negative result), then his or her cancer risk should be no greater than the population risk and high-risk screening is no longer necessary. Further, his or her children would also not be at risk for the mutation.
Cancer Treatment Decisions
As our understanding of the relationship between genetics and cancer expands, so does the range of cancer treatment options. Many new cancer treatments are being studied and developed to target particular types of genetic mutations found in cancers (both inherited and not inherited). This important work is helping to make treatments more personalized and effective.
Further, individuals with hereditary cancer risk may be at higher risk to develop a second cancer in the future. In planning the treatment course for a current diagnosis, knowledge of genetic risk may influence decisions about the type or extent of current treatments (for example, some people may consider more extensive surgery, such as bilateral mastectomies, to remove the current tumor as well as prevent the development of a future cancer). Also, some mutations are known to cause increased sensitivity to treatment-related side effects (such as radiation-induced damage), which may guide the treatment plan toward safer approaches.
Information for Family Members
For individuals who already have a diagnosis of cancer, another common concern is the implications for the health of loved ones. Genetic testing is most helpful when first performed in an individual who has had the cancer of concern (if a mutation exists in the family, this is where testing is most likely to positively identify it). If a causative mutation is identified, then testing of at-risk family members becomes much more straightforward to definitively confirm or rule out the associated cancer risks. If, on the other hand, testing does not confirm hereditary risk in a person with the cancer of concern, then further testing of family members is not usually recommended or useful, and family members should be followed based on the history of cancer in the family.
Genetic testing for cancer risk is a very personal decision, and is not right for everyone. Some people are concerned about the benefits versus potential risks, while others are more concerned with insurance or privacy issues. Click below to learn more about these common concerns pertaining to genetic testing:
If genetic testing is performed but does not identify a harmful genetic variant, or if testing is declined for any reason, DNA banking is another resource available to ensure the ability for future genetic testing of one’s DNA. This is primarily for the benefit of family members, and can allow for the most informative genetic testing and interpretation in the family (since it is always recommended to start testing in a family member who has had the cancer of concern). DNA banking is available through many laboratories throughout the country at relatively low cost, and can be facilitated by your genetic counselor or other providers. If you pursue DNA banking, it is important that you keep copies of the paperwork and inform your family members of this resource for them.
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