About Li-Fraumeni Syndrome

WHAT IS LI-FRAUMENI SYNDROME?

Li-Fraumeni Syndrome (LFS) is one of 7,000 rare diseases that affect 25-30 million Americans. It is estimated that over 500 families in the U.S. and over 1,000 multigenerational families worldwide have Li-Fraumeni Syndrome.

Li-Fraumeni Syndrome (LFS) is linked to a mutation in the TP53 tumor suppressor gene. There are many types of TP53 mutations. People with this mutation have a higher risk of developing cancer over their lifetime. LFS affects each individual differently, even within the same family. Some families with LFS have higher rates of cancer incidence, while others do not.

Video: Li-Fraumeni Syndrome (LFS) Basics

FACTS ABOUT LI-FRAUMENI SYNDROME

  • Over 500 cancers are considered rare
  • Most cancers seen in LFS are considered rare
  • ALL childhood cancers ARE rare
  • 50% of LFS cancers develop before the age of 30
  • A woman with LFS has a 90% or greater chance of developing cancer in her life. Much of this risk is due to breast cancer
  • A man with LFS has a 70% or greater chance of developing cancer in his life
  • People with LFS can develop many cancers over their lifetime
  • Approximately 80% of families with features of Li-Fraumeni Syndrome have a mutation in the TP53 gene
  • LFS is a dominant trait. This means if the mutation is passed to a child, their chance of getting cancer is greater than the normal population
  • Certain childhood cancers are linked to LFS – Choroid Plexus Carcinoma (brain tumors), Sarcomas (including Osteosarcoma), and Adrenocortical tumors
  • And finally…. not all people with LFS get cancer
  • learn more

WHO HAS LFS?

While Li-Fraumeni Syndrome does not affect one particular age, gender, or race, half of LFS cancers develop in children. LFS is usually passed from parent to child, but it can result from a new (de novo) mutation as well. A parent with LFS has a 50% chance of passing the mutation along to their children.

DO YOU HAVE LFS?

Li-Fraumeni Syndrome might be suspected if you have a personal history of multiple cancers, a family history of cancer or if certain cancers are seen in children or young adults in your family. The cancers most often seen in LFS are adrenocortical carcinomas, breast cancer, leukemias, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas, but LFS cancers can occur anywhere in the body.

SHOULD YOU BE TESTED?

Getting tested for a family cancer syndrome can be a daunting decision. A genetic counselor can help you weigh the risks and benefits of being tested for the TP53 mutation. Knowing whether or not you have the mutation can help you and your providers develop a personalized screening regimen designed to detect cancer at the earliest and most treatable stages. There is no one set protocol for screening LFS cancers, but there are screening recommendations based on the cancers frequently seen in the syndrome.

If you test positive for the TP53 mutation, it means you have an increased risk of developing cancer. It does not mean you will get cancer during your lifetime. There are many varying degrees of LFS and many people with a TP53 gene mutation live long, healthy lives.

Get

Support

Living with Li Fraumeni Syndrome can be isolating and overwhelming. By connecting LFS families with resources and others who have this rare syndrome, Living LFS provides awareness, support, and community.

Frequently Asked Questions (FAQ)

First of all, take a deep breath. It is a lot to take in. You are still the person you were yesterday, you just have another piece of information about your health and cancer risk. You do not have an expiration date. Take the time to gather your information, your thoughts and your care team.

Read the blog: Positively Living LFS: It’s Not a Death Sentence

Read the blog: 5 Life Lessons from People Likely to Get Cancer

Just like taking it one day at a time (sometimes one hour at a time), LFS presents many challenges. We try to protect our bodies, but we have to make tough choices. You may feel overwhelmed and that the choices contradict what you have been told. When making these decisions, we often use the saying, “You have to fight the shark closest to the boat.” If you have multiple sharks circling your boat, tackle the first and most life threatening first, you can’t fight off the next if you don’t beat the first.

Read the blog: The Shark Closest to the Boat

How would you want to be told? Each family dynamic is different. Since LFS is an autosomal dominant mutation, it can be passed to children. Genetic Counselors are excellent resources for not only helping you understand LFS, but for talking with family about the syndrome and other family members’ possible risk. 

Video: What can a genetic counselor do for someone with LFS?

TESTING

Cancer Genetics are very complicated. In the case of LFS, the disease is an inherited cancer predisposition. There are physical, social and emotional impacts when living with a genetic condition like Li-Fraumeni Syndrome. Genetic Counselors have special training that helps them support patients, evaluate the risks of their condition, and get the best care for their rare situation.

Read the blog: Genetic Counseling in LFS

Getting tested for Li-Fraumeni Syndrome is a very personal decision. There are many considerations: are you ready to know? Will knowing affect the way you approach health care or get you better care? Will insurance cover the test? Does knowing create undue stress? Everyone is different and Genetic Counselors can help you decide what the right path is for you. A couple things to consider: the test could always be negative, and once you know the results, you can’t unlearn them.

Global Genes: Becoming an Empowered Patient: A Toolkit for the Undiagnosed

Genetic Testing: Is This My Path to Diagnosis?

Another very controversial and personal decision is whether or not children should be tested for Li-Fraumeni Syndrome. Below, parents give insight into how they decided and how testing helped them.

Read the blog: Mutant Thoughts on Genetic Testing for LFS

LFS is linked to a mutation in the TP53 gene. If you are positive for the mutation, you have the mutation and you have an increased risk of cancer. Hopefully in the future, we will be able to associate risk with specific mutations, but for now we cannot predict if or when someone with LFS will get cancer, so we try to screen pretty comprehensively. There are many factors that lead to the development of cancer. Genetics is just one piece of a complex process.

Ambry Genetics:  Understanding Your Positive TP53 Genetic Test Result

So you are told you might have a genetic disorder with an insane cancer risk, you get up the nerve to take the test and then the results come back Variant of Uncertain Significance. Now what? The same information that led your providers to recommend testing, is still true. Basically right now, researchers cannot link the mutation you have to an increased risk of cancer. It doesn’t mean there isn’t one, we just don’t have the data yet. This is frustrating, but researchers in studies such as PROMPT are collecting data to try and figure this out.

Video: What is a VUS – a Variant of Uncertain Significance?

Mayo Clinic: I have a VUS (Variant of Uncertain Significance). Now what?

ABOUT LFS

On a basic level, Li-Fraumeni syndrome is an increased risk of cancer due to a mutation in the TP53 tumor suppressor gene. There is increase risk of rare sarcomas, brain tumors, breast cancers and adrenal cancer, as well as other tumors. Some people inherit LFS, others have LFS due to mutations as they were developing. There is no one size fits all with LFS and there are many mutations that can affect the p53 protein- some are more severe than others. If a person has the criteria for LFS but no identified mutation, it is called LFS-like. In Brazil, there is a predominant mutation that is linked to adrenal cancer and LFS. Other mutations such as CHEK2 are also associated with LFS.

Video: What is Li-Fraumeni Syndrome (LFS)?

Read the blog: Some p53 mutations are “nonsense”

DeNovo means you are the first in your family to have LFS. Although you can pass LFS along to your children, your parents do not have the mutation or increased risk of cancer.

On a very basic level, genetic mosaicism means a person has mixture of cells with different genetic make up. LFS Mosaics have some cells that have Tp53 mutations and some cells that do not, where as someone who inherits LFS from a parent will have mutations in all of their cells. Theoretically since mosaics do not have mutations in all of their cells, the cells that do not have mutant p53 are less likely to go rogue and turn into cancer or have the same risk of everyone else.

Video: What is Mosaicism? What is a Mosaic TP53 Mutation?

Read the blog: Mosaicism in Li-Fraumeni Syndrome

According to the World Health Organization, cancer is the second leading cause of human death globally. Elephants have 100 times more cells in their bodies than humans, but less than 5 percent of elephant deaths are linked to cancer. Why?

Elephants have 20 copies of the tumor-suppressing TP53 gene, while humans only have two. For those of us with LFS, one of those copies is mutated. If one copy of elephant TP53 gets mutated, there are 19 other copies to step up and help out with the damage.

According to Dr. Joshua Schiffman from Huntsman Cancer Institute, “If we can understand how these genomic changes are contributing to … cancer resistance, then we’ll be able to start thinking about how do we translate this to our patients?”

Video: What Do Elephants Have to Do With Li-Fraumeni Syndrome?

Read the blog: PBS Newshour on Elephants, Cancer and TP53

SCREENING

While there is still a psychological cost to learning that you carry a p53 mutation, many find benefit, both physically and psychologically, to screening. Screening allows for cancer to be found earlier in more treatable stages, which is empowering. There is also the psychological reassurance that come when nothing remarkable is found.

Read the blogs:

MRI 101

MRIs and kids

MRI contrast safety check

Radiation can cause damage to DNA, therefore it is recommended that those with LFS avoid ionizing radiation where possible. We try to use MRI where possible to reduce exposure, but sometimes X-rays, dental X-rays, CTs or PETs and other scans are necessary for diagnosis and treatment. It is important to weight the risks versus benefits of these scans with your provider.

Read the blogs: 

Mutants and Radiation: Trying to Understand Radiation in LFS

MRI vs. PET/CT

LIFESTYLE: Living with LFS

Although there is no diet recommended specifically for LFS, the American Institute for Cancer Research(AICR) has lots of information on what to eat to help prevent cancer as well as staying healthy during treatment.

Video: Hope Grows for Cancer Survivors Colleen Spees, PhD, MEd, RDN, FAND Medical Dietetics 

Infographic: 10 Recommendations for Cancer Prevention (American Institute for Cancer Research)

Living LFS moderates two private support groups on Facebook:

Li-Fraumeni Syndrome Support Group (for those with LFS)

Li-Fraumeni Syndrome Family and Friends (for family and friends of those with LFS) 

Simply send a request to join the appropriate group and a moderator will be in touch. The founders of Living LFS met and formed friendships through this support group and it has been a lifeline for many newly diagnosed or veterans during the most dire times. Due to the worldwide reach of the internet, we say someone is usually awake somewhere if you need to reach out to speak with someone who has been there and understands what it is like to LIVE LFS. 

More support resources

This list of frequently asked questions is a work in progress. If you have a question not yet covered here please contact us.

History of LFS

“P53 is a tumor suppressor gene. The gene encodes for a protein that monitors the state of the cell. If something goes wrong, it stops the cell from dividing or causes the cell to commit suicide.

I call it the “guardian of the genome” as it is the molecule that seems to keep cells normal. It is one of our big defenses against cancer.

In rare human families that inherit a defect in p53 gene function, we see that family members develop cancer much more frequently than normal, showing how important p53 is for most of us in preventing cancer.”

-Sir David Lane

What we call Li-Fraumeni Syndrome (LFS), began as a question mark during an entirely different study on cancer. LFS is named after two doctors who made the connection between specific cancers in certain families. Now, 40 years later, through the passions and efforts of many researchers and clinicians around the world, the history, the various functions of p53, and its connection to LFS are still being uncovered.

In 1967, during the course of conversation at the future NIH, Drs. Frederick P. Li, Joseph Fraumeni and Robert Miller noticed a particular family popped up. This family had three small children who had soft tissue sarcomas, a very rare type of tumor. When Dr. Li and Dr. Fraumeni talked to the patient’s family more, they found other cancers in other members too, such as breast cancer and sarcomas. Three families had two siblings and one family had two cousins with sarcomas. Beyond that rare occurrence, three of the mothers of the sarcoma children had breast cancer. Further study found 24 kindreds with numerous cancers, which they labelled SBLA (Sarcoma, Breast, Leukemia, Adrenal) Syndrome, now known as Li-Fraumeni Syndrome. The scientific article, like the syndrome, was emphasized with a question mark.

“Whenever possible, we collected biospecimens from family members in hopes of finding a mechanism that might explain susceptibility to such an array of different tumors. Success was limited until 1990 when a study was conducted with Stephen Friend and David Malkin at Harvard, along with Louise Strong at M.D. Anderson. The study found germline mutations of the p53 tumor suppressor gene in several consecutive families. The syndrome continues to be of special interest to basic and clinical scientists, especially since somatic mutations of p53 are known to occur in a high proportion of cancer patients in the population.”

-Dr. Joseph Fraumeni
Voices A Conversation with Joseph Fraumeni Epidemiology. Nov. 2016

“As long as you have supportive mentors and collaborators, there is no need to worry about getting lost in the crowd. It is helpful to see how team science works, and there are always projects, including spinoffs or add-ons, in which a young investigator can play a lead role.”

-Dr. Joseph Fraumeni
Voices A Conversation with Joseph Fraumeni Epidemiology. Nov. 2016

DISCOVERY OF p53

In 1979, Sir David Lane and colleagues at the Imperial Cancer Research Fund laboratories in the UK discovered a 53 kilodalton protein that became known as p53.

“We were working on a virus that could cause cells in culture to start to multiple uncontrollably, much like cancer cells. It was a very small virus, called SV40, and it only made a single protein, a so-called large T-protein.

Surprisingly that one protein expressed in a cell was enough to cause it to behave like a cancer cell. It became clear from that moment that SV40 must interact in some very subtle and complicated way with the host cell to make it change its behavior.

I then used immunological methods to “go fishing” so that I could figure out what was going on intra-cellularly to interact with the T antigen. Turns out that the culprit was the p53 protein.”

-Sir David Lane

Meanwhile, across the pond at Princeton University, Arnold Levine and his colleagues also identified p53 as a tumor suppressor.

By the early 1980’s, many researchers immersed themselves in the viral theory of cancer, others took an immunological approach. Studies on p53 seemed to stall until the discovery of cloning in the mid 1980s. Multiple labs tried to fit TP53 into the “oncogene” category, yet kept coming up short.

“A review of the literature reveals that there were signs that p53 was not a conventional oncogene, although these were often disregarded at the time and interpretted as exceptions to particular models. It is important to remember that the current classification of p53 as a tumour suppressor gene is not conclusive. Wild-type p53 acts as a negative regulator of cell proliferation, but mutant p53 must be considered to be an oncogene with additional functions, which can vary from one mutant to another.”

-Thierry Soussi, 2010

In 1987, Dr. Li gave a keynote address in Japan at the Princess Takamatsu Cancer Research Fund Symposium. He discussed Li-Fraumeni Syndrome and the series of events that leading to the identification of this hereditary cancer syndrome,

“The disorder affects only a few families and has almost no public health impact. The reason is that several major forms of childhood cancer are involved and that another component, breast cancer is the commonest neoplasm in many parts of the world. Our approach is to study the rare, but hopefully informative, families with this cancer syndrome to gain new insights into genetic mechanisms involved in breast cancer and childhood neoplasms in general.”

-Thierry Soussi, 2010
Dr. Li realized something very important about not only cancer, but also LFS. He did not see the rarity of LFS as a problem, but rather a key to finding out important pieces of the bigger cancer puzzle.

“It’s[TP53] the single most common mutation in human cancer,” Levine remarks in a telephone interview. “If we can learn how to really harness it and work it right, we can try to get back at the cancers and kill them.”

-Arnold Levine, 1999

1990: Science Article

Then in the 1990’s, TP53 shot to stardom due to out-of-the-box thinking by several brilliant young scientists and a cover on Science Magazine. TP53 became known as a very complicated Tumor suppressor: “Guardian of the Genome”.

Stephen Friend…. had two things going at the same time. He was working with Fred Li on a family that they had where they actually could do linkage analysis and he was working with us on these fibroblasts to see if…he could sequence the p53 gene. He could actually look for specific mutations. He was looking for mutations in this family of Fred’s in the normal DNA and he was looking at the immortalized fibroblasts to see if what had happened was we had an inherited mutation and perhaps an acquired mutation that had occurred in this immortalization and that would make sense that you would then… get a tumor.”

-Louise Strong, 2012

Psychosocial Impact and Genetic Testing

“So we had to set up a psychosocial study to measure the impact of this information so we could get IRB approval, but the chills of actually knowing that and then looking at the pedigree of four or five generations of people who died of cancers, it literally still gives me chills today sometimes. It was just really scary to know that at a time when you’ve just never been in a position to know that much about somebody—somebody’s family—or to know how it was going to change their lives—or do they want to know? So it was very exciting. Certainly by far the most dramatic of anything in my scientific career.”

-Louise Strong

Screening

“We are trying to put together a different team to develop a cancer screening program for these patients. Over the years I’ve always brought that up to our imaging people and always been told that you cannot—for the tumors we were worried about—brain tumors, bone tumors, sarcomas—that you couldn’t image it before it would be causing some kind of symptom. Now imaging has improved a lot in the last few years, too—particularly MRI. CT has improved, too, but it has a lot of—it has a fair amount of radiation associated with it. About a year ago a group in Canada put together a screening program for individuals who carried mutations in this p53 gene, including children and adults.”

-Louise Strong, 2012

While there is a psychological cost to learning that you carry a p53 mutation, many find benefit, both physically and psychologically, to screening. Screening allows for cancer to be found earlier in more treatable stages, which is empowering. There is also the psychological reassurance that comes when nothing remarkable is found. Dr. Malkin, an oncologist and director of Cancer Genetics at Toronto’s Hospital for Sick Children, studied screening of 89 patients in 2011 found those who underwent surveillance with what affectionately became known as the Toronto Protocol, had a better five year survival rate than those who did not participate.

“What this shows is that in an albeit uncommon cancer-predisposition syndrome, it is possible using common clinical tools to detect cancers early and by so doing to intervene early and improve survival dramatically,”

“There is currently no way to predict which individual with LFS will develop cancer, when that cancer might occur, or what types of cancer they will develop”

“Our goal is to learn enough about the disease to be able to accurately predict these things – and hopefully stop them before they happen.”

-David Malkin

Elephants: 2013 Conference in Boston

“By all logical reasoning, elephants should be developing a tremendous amount of cancer, and in fact, should be extinct by now due to such a high risk for cancer,” says Schiffman. “We think that making more p53 is nature’s way of keeping this species alive.” “Nature has already figured out how to prevent cancer. It’s up to us to learn how different animals tackle the problem so we can adapt those strategies to prevent cancer in people.”

-Joshua Schiffman, 2015

Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969;71:747–752

Epidemiology. 2013 Nov;24(6):929-33. doi: 10.1097/EDE.0b013e3182a56987. A conversation with Joseph F. Fraumeni, Jr. Interviewed by Robert N. Hoover.

Soussi, Thierry. “The history of p53. A perfect example of the drawbacks of scientific paradigms.” EMBO reports vol. 11,11 (2010): 822-6. doi:10.1038/embor.2010.159

International Cancer Symposium subsidized by the Princess Takamatsu Cancer Research Fund (November 17–19, 1987, Tokyo).

https://www.nytimes.com/2015/06/22/health/frederick-p-li-who-proved-a-genetic-cancer-link-dies-at-75.html Dr. Frederick Li, Researcher Who Proved a Genetic Link to Cancer, Is Dead at 75

https://www.the-scientist.com/news/taking-aim-at-p53-researchers-are-targeting-the-tumor-suppressor-with-vectors-viruses-and-small-molecules-56681 Levine, Lane

de Almeida, John. (2003). An Interview with Dr. David Malkin, Medical Oncologist. University of Toronto Medical Journal.

http://library.mdanderson.org/ohms-viewer/viewer.php?cachefile=Strong_Louise_20120808.xml#segment1605
Louise Strong

https://healthcare.utah.edu/publicaffairs/news/2015/10/10-08-15_Why_Elephants_Rarely_Get_Cancer.php
Joshua Schiffman

Regular cancer screening program boosts survival rates for Li-Fraumeni patients
Protocol boosts survival for Li-Fraumeni patients
Sheryl Ubelacker The Canadian Press Aug 5, 2016
https://www.chroniclejournal.com/life/national_life/regular-cancer-screening-program-boosts-survival-rates-for-li-fraumeni/article_6d60bd3e-5abf-5d20-8123-db4bd1079fbb.html

https://www.tfri.ca/our-research/research-project/early-detection-and-prevention-of-cancer-in-li-fraumeni-syndrome
David Malkin

Nature Poster: https://www.nature.com/reviews/posters/p53/pdf/p53_poster.pdf

Varda Rotter, Israel https://www.weizmann.ac.il/mcb/Varda/sites/mcb.Varda/files/p53story.pdf

David Lane : Lane, David, and Arnold Levine. “p53 Research: the past thirty years and the next thirty years.” Cold Spring Harbor perspectives in biology vol. 2,12 (2010): a000893. doi:10.1101/cshperspect.a000893

https://www.news-medical.net/news/20130722/p53-and-cancer-research-an-interview-with-Professor-Sir-David-Lane-Scientific-Director-of-the-Ludwig-Institute-for-Cancer-Research.aspx