Living with LFS has many challenges, stresses, and choices. We do not get to choose our DNA or IF we will get cancer. We can choose whether or not to screen or make lifestyle choices that affect our health. In a recent perspective article in the New England Journal of Medicine, Shekinah N.C. Elmore, M.D. shares her experience with LFS as a patient, medical student and doctor. Most importantly, Dr. Elmore discusses the devastation, the emotional aspects of learning to live as an “Onco-mutant” and how it changed her outlook on life and health care. The link below will take you to the article, P53 and Me.
Few things are more frustrating than looking for answers and getting the response- we don’t know. Sometimes, a person agonizes over the decision to be tested for a hereditary cancer syndrome like LFS, finally getting tested just to know for sure. Unfortunately the results aren’t always a clear cut; Yes, you have LFS or No, you do not have LFS.
There are thousands and thousands of changes that can occur to our DNA, called mutations. Not all mutations are harmful- whether or not the mutations are “bad” is a personal opinion. There are mutations that we just don’t know if they are harmful or harmless, in the case of LFS, we don’t know if the mutation is associated with cancer. They are called Variants of Uncertain Significance (VUS), also known as Variants of Unknown Significance (still VUS), or Unclassified Variants.
Li-Fraumeni Syndrome is associated with mutations in the TP53 gene. TP53 makes a tumor suppressor, so if the tumor suppressor doesn’t work right, we sprout tumors. There are many spots on the DNA, where mutations can occur. Some change the way the gene works, some do not. Sometimes the gene only works a little bit. For more reading on mutations and how they affect us, you can read our blog “Some MUTATIONS are NONSENSE“.
When classifying variants (changes in DNA/mutations) there is a scale from 1-5 – Benign to Pathogenic. Benign (B9 to experienced mutants) means not harmful or more importantly not malignant. Pathogenic means to cause a disease- in our case, cancers.
Benign means there is no change caused by the variant.
Likely Benign means suspected to not cause disease.
Uncertain are VUS (Variants of Uncertain Significance) this means there is not enough data to know if the mutation will cause disease or not.
Likely Pathogenic means the variant is suspected to cause disease.
Pathogenic means the variant is known to cause disease.
Genomic Variant Scale from ASHG.org
The American Society of Human Genetics (ASHG) advises that VUS should not be used for decision making, they are neither good nor bad, and all medical decisions should be based on medical findings and family history. This does not mean you are negative for a mutation, it simply means there is a mutation there and that we do not have enough information to momentarily identify what the risk is. The best bet is to consult with a trusted geneticist or genetic counselor (www.nsgc.org) to evaluate your risk based on what you do know – your medical history, your family history, and other relevant factors.
Things to Remember:
You cannot interpret what is not known. Li-Fraumeni Syndrome is rare, we just don’t have the research numbers to know if VUS are linked to cancers. Not everyone with LFS linked mutations get cancer. We know some mutations are linked to certain cancers in LFS but there is still a lot of uncertainty. Participating in studies, such as PROMPT help record data and could help predict if certain VUS might be linked to risk of certain cancers or not.
Focus on what you can control. You can control diet, exercise, and other contributing factors to a healthy lifestyle. Although we can not control mutations, we can try to reduce our risk. A genetic counselor can help you evaluate risk and decide what and if a screening regimen would be good for you. Many people with LFS follow the Toronto Protocol, however, the best regimen is the one that works best for you, your risk, insurance coverage, and lifestyle.
As we learn more, classifications can change. When TP53 was first discovered, it was thought to be an oncogene, a gene that causes cancer. After decades of research, it was reclassified as a tumor suppressor gene. Keeping up with current research can help you advocate for yourself and live LFS.
LLFS Board Member Andi connected with Wendy Kohlmann, MS, CGC, a licensed genetic counselor at the University of Utah Huntsman Cancer Institute. In this excerpt from her interview for the Learning Li-Fraumeni Syndrome podcast, she explains what it means when your genetic test results show a VUS: a variant of uncertain significance or variant of unknown significance.