Variants of Uncertain Significance(VUS) in LFS

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.

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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.

  1. Benign means there is no change caused by the variant.
  2. Likely Benign means suspected to not cause disease.
  3. Uncertain are VUS (Variants of Uncertain Significance) this means there is not enough data to know if the mutation will cause disease or not.
  4. Likely Pathogenic means the variant is suspected to cause disease.
  5. Pathogenic means the variant is known to cause disease.

 

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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.

Like our page to see more segments from Learning Li-Fraumeni Syndrome, a new video and audio podcast presented by Living LFS: https://www.facebook.com/LivingLFS/

Resources and more reading on VUS:

American Society of Human Genetics on VUS

Mayo Clinic pdf on VUS

Think Genetic LFS VUS


COTI-2 – Big Excitement surrounding a SMALL Molecule.

One of the most exciting presentations at the REACH 16 International LFS Conference was information presented on COTI-2, a novel small molecule that helps repair some mutant p53. Dr. Wayne Danter is the Co-Founder, President and CEO of Critical Outcome Technologies, Inc., an Ontario based biopharmaceutical company that works to  “be instrumental in saving thousands of lives by enabling accelerated development of new effective treatment options.” For rare communities, like ours with Li-Fraumeni Syndrome, we truly appreciate any options that could help us. There is much excitement surrounding this small molecule, not just for those with LFS who often have treatment resistant, aggressive cancers, but for the greater cancer community. This is a groundbreaking and promising approach. A few years ago, Metformin became the first chemoprevention drug studied in LFS patients and empowered many to participate in the study. COTI-2 is a small molecule that is giving people with LFS big hope and for many this hope cannot come soon enough.

 

What is COTI-2?

COTI-2 is the name of a drug that was discovered by a computer program at Critical Outcome Technologies, called CHEMSAS.  It works by refolding certain mutant p53 in a way that helps p53 work again. COTI-2 can be taken orally and does not appear to be toxic to healthy p53 or other healthy cells. It also seems to work well with some traditional chemotherapy agents like cisplatin used to treat many LFS cancers.

Critical Outcome Technologies: criticaloutcome.com About COTI-2

How Does COTI-2 WORK?

COTI-2 works on mutated p53. When the p53 protein is made(transcribed) from the incorrect directions(mutant DNA) – sometimes it creates a less functional protein p53 or sometimes the protein doesn’t work at all. Say you have the word COT. If you change the O to an A, the word is now CAT, a word that has a different meaning but still a word. If you replace O with a C, then you have CCT. Not really a word. This is part of the reason we see so many different cancers in LFS, not all mutations are the same, some are more severe than others. Not only do the mutations make different protein shapes, the p53 protein itself has many jobs.  Some people with LFS have many cancers, others have one or two and yet others never get cancer at all. If you want to learn more about mutations, check out our blog post Some p53 Mutations are Nonsense.

Why is COTI-2 Important?

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Critical Outcome Technologies: criticaloutcome.com About COTI-2

Of course a drug that can restore p53 is important to people with germline TP53 mutations. Clinical Trials are necessary to show that drugs are safe and effective. These trials take time and participants. The idea is that if COTI-2 is both safe and effective,  it could not only be used to treat many rare LFS cancers, but also the 50% of tumors among the general population that have mutated p53. Our LFS population is very small compared to the overall cancer community and it is part of the reason why getting trial data and targeted molecules for LFS is difficult. By creating a molecule that not only helps our rare population, but a good percentage of cancer patients in general, we will see progress.

 

How has COTI-2 been Tested?

COTI-2 molecules were chosen via computer simulation. The program looked at the structure of mutated p53 then tried to find a novel molecule that would repair the p53.  COTI-2 was used to treat cancer cells lines in petri dishes,  then p53 mutations were introduced into mouse fibroblast cells and then treated with the COTI-2 and then mouse animal models. Recently humans at MDAnderson with gynecological cancers were given Coti-2 as part of a Phase 1 trial and a direct result of COTI-2 receiving orphan drug status is important for trials like these because it facilitates the development of drugs for rare diseases like LFS that affect less than 200,ooo individuals. Researchers found, not only did COTI-2 decrease the amount of mutated p53, the amount of normal p53 increased and it was tolerated very well by the participants. Even at low doses, they saw a good response.

At the conference, Dr. Danter created much excitement when he announced they were moving ahead with the next trial in 2017. Although it may still be years away from being approved, this is a really great step. This may not be a magic bullet and cure all LFS cancers, but the hope and promise of the possibility is valued dearly and appreciated in our LFS community.

Resources

http://www.criticaloutcomeblog.com/blog-posts/p53-li-fraumeni-syndrome-and-coti-2

http://www.news-medical.net/news/20130708/p53-restoration-of-function-drug-candidate-an-interview-with-Dr-Wayne-Danter-MD-FRCPC-President-and-CEO-of-Critical-Outcome-Technologies.aspx#.V2mlICTeunI.google

Clinical Trial- https://clinicaltrials.gov/ct2/show/NCT02433626

http://criticaloutcome.com/wp-content/uploads/2015/12/151205_Orphan-Drug-Application-LFS.pdf

http://www.pharmaceuticalonline.com/doc/fda-grants-orphan-drug-status-to-coti-s-ovarian-cancer-drug-coti-0001

Dr. Danter’s Presentation