Patient and Family Resources

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a hereditary condition that causes an increased risk of developing certain types of cancers, with a lifetime risk as high as 73% for men and 90% for women. People with Li-Fraumeni syndrome are often diagnosed with cancer at a young age and may develop multiple different cancers in their lifetime. It is important for people with LFS to be closely monitored for cancer development starting at a young age.

What causes Li-Fraumeni syndrome?

Li-Fraumeni syndrome occurs due to a mutation in the TP53 gene. The TP53 gene normally helps control the growth of cells in our body. When someone has a mutation in the TP53 gene, the gene no longer can control cell growth resulting in an increased risk of uncontrolled growth of cells, which leads to the development of cancer.

Most common types of cancers seen in families with LFS

  • Sarcomas of the soft tissue (such as fat tissue, muscles, or nerves)
  • Osteosarcomas (sarcomas of the bone)
  • Brain tumors
  • Breast cancers
  • Adrenocortical carcinomas (cancer of the adrenal gland)

Other cancers that can also be seen in people with LFS

  • Melanoma (an aggressive type of skin cancer)
  • Colon cancer
  • Lung cancer
  • Leukemia (typically acute myeloid leukemia (AML) in children)

How is Li-Fraumeni syndrome inherited?

A person with a mutation in the TP53 gene has a 50 percent chance of passing the mutation on to their children. Both males and females have an equal risk to inherit the mutation from a parent who has the TP53 mutation. TP53 mutations do NOT skip generations.

A mutation in the TP53 gene can occur at the time of conception, called a “de novo” mutation. This means the mutation randomly developed when they were conceived but was not inherited from either parent. In these cases, the person usually does not have a family history of cancer concerning LFS. However, this person is at risk to develop LFS-associated cancers and pass the mutation on to children. De novo mutations in the TP53 gene occur in about 7-20 percent of people with LFS.

Genetic testing for Li-Fraumeni syndrome

Meeting with a genetic counselor to discuss your personal and family history will help determine if genetic testing for Li-Fraumeni syndrome is appropriate. Genetic testing will thoroughly examine the TP53 gene to determine whether or not there is a mutation in the gene.

Genetic testing for LFS is most often recommended when there is:

  • Known family history of Li-Fraumeni syndrome
  • Personal or family history of a rare cancer associated with LFS
  • Personal or family history of cancer diagnosed at a very young age, including in children
  • Personal and/or family history of cancer that meets criteria for LFS

After being diagnosed with Li-Fraumeni syndrome

You and your providers should work together to create a personalized cancer screening and risk-reduction plan. Increased cancer screening helps in detection of cancer at an early and often more treatable stage. People with Li-Fraumeni syndrome are encouraged to be followed by a clinic or a physician who is well-versed with LFS and its associated cancer risks and management guidelines.

Screening guidelines for men and women with LFS

  • Yearly comprehensive physical exams and neurologic evaluation
  • Yearly dermatological exams
  • Yearly whole body MRI and brain MRI
  • Colonoscopy screening every 2-5 years starting at age 25

Recommendations for breast cancer screening and risk reduction for adult women

  • Yearly clinical breast exams
  • Yearly breast MRI staring at age 20
  • Yearly mammogram starting at age 30
  • Consideration of risk-reducing mastectomy (removal of both breasts)

What to avoid if you are diagnosed with LFS

People with a TP53 mutation should avoid radiation exposure whenever possible, as radiation exposure increases the risk for cancer development.

Additionally, people with LFS should avoid tobacco use, excessive sun exposure, and exposure to other known or suspected cancer-causing substances.

Additional resources and support

Some benefit from additional resources and support, such as connecting with others who have also been diagnosed with LFS.

If you are diagnosed with LFS, meet with a physician with LFS expertise in the Smilow Cancer Genetics and Prevention Program at Yale New Haven Hospital to create a personalized screening and prevention plan.

Hereditary Gynecological Cancers

Gynecological cancers include cancers of the female reproductive organs including the uterus, ovaries, fallopian tubes, and cervix.

The genes associated with hereditary breast and ovarian cancers are the BRCA1 and BRCA2 genes. Understanding whether you have inherited a mutation in one of these genes can help you and your doctors develop management recommendations. Management options may include developing a cancer screening plan that can detect cancer at an early stage or risk-reduction surgery to reduce the risk of developing cancer.

Ovarian Cancer

The lifetime risk of ovarian cancer in the general population is 1-2 percent. In women with a mutation in the BRCA1 gene, the lifetime risk to develop ovarian cancer is 40-60 percent. In women with a mutation in the BRCA2 gene, the lifetime risk to develop ovarian cancer is 15-30 percent. Women with a BRCA1/2 mutation also have an increased risk to develop cancer of the fallopian tube and peritoneum (the lining of the abdomen).

Uterine Cancer

The lifetime risk of developing uterine cancer in the general population is 2-3 percent. About 5 percent of uterine cancer is hereditary. At this time, studies suggest that women with mutations in the BRCA1 gene may have a slightly increased risk to develop a uterine papillary serous cancer (UPSC).

MLH1, MSH2, MSH6, PMS2 genes

The MLH1, MSH2, MSH6, PMS2 genes are associated with Lynch syndrome. The risk of ovarian and uterine cancer is different for each of Lynch syndrome gene.

Genes Ovarian Cancer Risk Uterine Cancer Risk
MLH1 4% - 20% 34% - 54%
MSH2 8% - 38% 21% - 57%
PMS2 Similar to risk in general population 13% - 26%

STK11 gene

The STK11 gene is associated with Peutz-Jeghers syndrome. Those who have the STK11 gene are at a lifetime risk of up to 21 percent to develop ovarian cancer, 9 percent to develop uterine cancer, and 10 percent to develop a specific, rare and aggressive type of cervical cancer, called adenoma malignum.

Other genes associated with hereditary ovarian cancer

  • BRIP1 gene: lifetime risk in women with mutations in the BRIP1 gene is up to 10 percent.
  • RAD51C and RAD51D genes: lifetime risk in women with mutations in the RAD51C or the RAD51D gene is up to 13 percent.
  • ATM gene: women with an ATM mutation have a less than 3 percent lifetime risk.
  • PALB2 gene: women with a PALB2 mutation may have an estimated 3-5 percent increased risk.
  • DICER1 gene: mutations in DICER1 gene are associated with an increased risk of rare types of ovarian tumors, such as Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, and gynandroblastomas.

Other genes associated with hereditary uterine cancer

PTEN gene: mutations in the PTEN gene are associated with PTEN Hamartoma Tumor syndrome. The lifetime risk in women with a mutation in the PTEN gene is an estimated 5-10 percent.

Hereditary Prostate Cancer Prostate Cancer

Hereditary Prostate Cancer Prostate Cancer is the second most common cancer diagnosis in men. One out of every nine men will be diagnosed with prostate cancer in their lifetime. Most men are diagnosed with prostate cancer in their mid-60s.

Men over the age of 50 should discuss routine prostate cancer screening with their primary care providers. Men with certain risk factors in their family may be at risk of having a hereditary predisposition to prostate cancer. Identifying men with a hereditary predisposition to develop prostate cancer can help guide the course of their cancer treatment or preventative cancer screening, provide an explanation for their family history of cancer, and clarify their risks for other cancers.

Most prostate cancers are slow-growing and less likely to require extensive treatment. Pathology uses a Gleason score to grade the aggressiveness of prostate cancer. A higher Gleason score indicates a more advanced prostate cancer that may require a more extensive treatment and is at risk to spread to other areas of the body.

Hereditary predisposition to prostate cancer

While the majority of prostate cancers are not hereditary, an estimated 12 percent of advanced prostate cancer is due to a hereditary cause. Indicators that increase suspicion of a hereditary predisposition to prostate cancer include:

  • Metastatic prostate cancer: prostate cancer that spread to other sites including the bones and lungs.
  • Prostate Cancer with a Gleason score ≥7: a score of 7 or higher indicates a more aggressive cancer which could be suspicious of a hereditary predisposition.
  • Family history of breast, ovarian, or pancreatic cancer
  • Multiple (3+) siblings or relatives on the same side of the family with prostate cancer.
  • Ashkenazi Jewish ancestry

Genetic Testing

We encourage all people who are interested in undergoing genetic testing to meet with a genetic counselor. A cancer genetics consultation provides you the opportunity to discuss your personal and/or family history of cancer. During the appointment, the genetic counselor can help you determine whether genetic testing is appropriate for you, discuss the available genetic testing options, and the risks, benefits, limitations, and other implications of genetic testing. Genetic testing is typically performed on a blood or saliva sample.

Some may also use this information in making reproductive decisions. However, some who have genetic testing may experience depression, anxiety, or fear. Discussing all of these considerations and the possible outcomes of genetic testing with a genetic counselor can assist you in making the decision that is best for you.

Please contact the Smilow Cancer Genetics and Prevention Program at 203-200-4362 to learn about the process of setting up a genetic counseling appointment.