Families Predisposed to Cancer: The Li-Fraumeni Syndrome

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Li-Fraumeni syndrome, or LFS, is a genetic condition that predisposes individuals to a variety of different cancers. People with LFS often develop these cancers earlier in life than what is typical in the general population. There may also be a greater risk of second or subsequent cancers in LFS.

The syndrome was first recognized in several families that developed a wide variety of different cancers, especially sarcomas, early in life. Additionally, family members appeared to be more likely to develop multiple, new and different cancers over the course of a lifetime. Frederick Li and Joseph Fraumeni, Jr, were doctors who first reported on these findings in 1969, and that is how LFS got its name.

Why the Higher Risk of Cancers?

People with Li-Fraumeni syndrome have a higher risk of cancer because they have inherited what’s known as a germline mutation in an important gene called TP53.

A germline mutation is a genetic change that has occurred in the germ line of the affected individual’s parents—that is, a mutation initially occurs in the cells in the ovaries or testes that give rise to egg and sperm. Mutations in these cells are the only kinds of mutations that can be passed directly to the offspring at the time of conception when the egg and sperm meet to form a zygote. Thus, germline mutations will affect every cell in the body of the new offspring; in contrast, somatic mutations develop somewhere in an individual at some point after conception, or much, much later, and they affect a variable number of cells in the body.

The key germline mutations in families with LFS are those that affect the function of the TP53 gene. In the world of cancer research, the TP53 gene is so critical that it’s been called the “guardian of the genome.”

TP53 is a tumor suppressor gene—that is, it’s a gene that protects a cell from one step on the path to cancer. When this gene mutates such that it doesn’t work as it’s intended, or so that its function is greatly reduced, the cell can progress to cancer, often in combination with other genetic changes. Testing for TP53 germline mutations was first developed in 1990 when the link between p53 and LFS was confirmed. Since then, nearly 250 mutations throughout the  TP53 gene have been detected.

A mutation in another gene, hCHK2, has also been associated with LFS, however, its significance is unclear. The hCHK2 gene is a tumor suppressor gene that is activated in response to DNA damage. Only a small number of families carry this mutation, and those affected have a similar range of malignancies as those with the TP53 mutations.

How High Is the Risk?

It has been estimated that, overall, a person with LFS has a 50 percent chance of developing cancer by the age 40 and as much as a 90 percent chance by the age of 60. If you have LFS, your individual risk depends in part on whether you are male or female, with females generally having a higher risk than males.  

If you look at the lifetime risk of cancer in men and women with LFS at age 50, then the risk of developing cancer breaks down as follows: 93 percent for women and 68 percent for men. If they do develop cancer, women also tend to develop that cancer at an earlier age: 29 years, on average, versus 40 years of age in men.

The higher risk in females is mainly due to early-onset breast cancer, according to the study by Mai and colleagues. These researchers also found that, among women who tested positive for TP53 mutations, breast cancer was by far the most common malignancy. The cumulative breast cancer incidence was about 85 percent by age 60. In the same study, breast cancer risk increased significantly during the woman’s 20s, confirming that breast cancer screening starting at 20 years of age is a good practice in women with LFS.

This level of risk for TP53 mutations is comparable to that seen in females with germline mutations in BRCA1 and BRCA2—these genes rose to prominence with popular reporting about genetic testing of BRCA1/2 mutations and preventive mastectomies (by celebrities such as Angelina Jolie).

What Are the Core Cancers Involved?

Any cancer can develop in any individual at any time. However, people with LFS are known to have early cancer diagnoses and high lifetime risk of several “core” kinds of cancer, including the following:

  • Osteosarcoma—the most common type of cancer that starts in the bones
  • Soft-tissue sarcomas—a type of cancer that develops from certain tissues, like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues
  • Early-onset breast cancer
  • Brain tumors
  • Leukemia—a cancer of the blood-forming cells
  • Adrenal cortical carcinoma—a cancer of the adrenal cortex, which is the outer layer of the adrenal glands. The adrenal glands lie on top of the kidneys and play an important role in various hormonal functions.

In a 1997 study by Kleihues, the most commonly identified sarcoma in LFS was osteosarcoma, corresponding to 12.6 percent of cases, followed by brain tumors (12 percent) and soft tissue sarcomas (11.6 percent). Of the soft tissue sarcomas, rhabdomyosarcomas (RMS) are the most frequently identified. Other less frequent sarcomas reported include fibrosarcomas (which is no longer considered a true entity), atypical fibroxanthomas, leiomyosarcomas, orbital liposarcomas, spindle cell sarcomas, and undifferentiated pleomorphic sarcomas. Hematological neoplasms, or blood cancers (such as acute lymphoblastic leukemia and Hodgkin's lymphoma) and adrenocortical carcinomas occurred at a frequency of 4.2 and 3.6 percent, respectively.

As more families with genetic mutations typical of LFS have been identified, many more cancers have been implicated.

The LFS cancer spectrum has expanded to include melanoma, lung, gastrointestinal tract, thyroid, ovarian, and other cancers.

Based on traditional assessments, the risk of developing soft-tissue sarcoma and brain cancer seems to be greatest in childhood, while the risk of osteosarcoma may be highest during adolescence, and the risk of female breast cancer increases significantly around age 20 and continues into older adulthood. These statistics are subject to change, however, since the practices of testing for cancer-predisposition genes have been evolving.

How Is Li-Fraumeni Syndrome Defined?

There are different criteria and definitions for this syndrome. Some are more inclusive than others. Classic LFS is the most restrictive definition, as it requires a sarcoma diagnosis before age 45, while subsequent definitions such as the Chompret criteria attempted to fold in evolving scientific knowledge about tumor types and about ages at diagnosis.

Classic LFS criteria:

  • You are diagnosed with a sarcoma (a cancer type that includes cells of muscle/skeletal/joints/fat origin) before age 45 years and
  • A first-degree relative (parent, sibling or child) with any cancer diagnosed before age 45 years and
  • Another first- or second-degree relative (includes aunts, uncles, and more) with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age.

Li-Fraumeni-like (LFL) criteria:

  • The LFL criteria cast a wider net to include other cancer types and include some relatives diagnosed after age 45, and there are two different definitions in use:
  • Birch definition: You are diagnosed with any childhood cancer or sarcoma, brain tumor, or adrenocortical carcinoma diagnosed before age 45 years and a first- or second-degree relative with a typical Li-Fraumeni cancer (sarcoma, breast cancer, brain tumor, adrenocortical carcinoma, or leukemia) at any age and a first- or second-degree relative with any cancer before age 60 years.
  • Eels definition: You have 2 first- or second-degree relatives with Li-Fraumeni–related malignancies (sarcoma, breast cancer, brain tumor, leukemia, adrenocortical tumor, melanoma, prostate cancer, pancreatic cancer) at any age.

Chompret criteria:

  • You have a tumor belonging to the Li-Fraumeni tumor spectrum (soft-tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or bronchoalveolar lung cancer) before age 46 years and at least one first- or second-degree relative with a Li-Fraumeni tumor (except breast cancer, if you have breast cancer) before age 56 years or with multiple tumors or
  • You have multiple tumors (except multiple breast tumors), 2 of which belong to the Li-Fraumeni tumor spectrum and the first of which occurred before age 46 years or
  • You are diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history.

According to the review of LFS by Schneider and colleagues, at least 70 percent of individuals diagnosed clinically (that is, using definitions such as those above) have an identifiable harmful germline mutation in the TP53 tumor suppressor gene.

Management of Cancers

If an individual with LFS develops cancer, routine cancer treatment is recommended, with the exception of breast cancer, in which mastectomy, rather than lumpectomy, is recommended in order to reduce the risks of a second breast cancer and also to avoid radiation therapy.

Those with LFS are advised to avoid radiation therapy whenever possible in order to limit the risk for secondary radiation-induced malignancies. However, when radiation is considered medically necessary to improve the chance of survival from a given malignancy, it may be used at the discretion of the treating physician and patient.

Screening and Surveillance

There has been a growing call for experts to form a consensus about how families with FLS should be screened and cared for. Unfortunately, while the science is evolving rapidly, no such consensus yet exists in all areas.

The frequency of harmful TP53 mutations in the general population is unknown, and the true frequency of FLS is unknown. Estimates vary between 1 in 5,000 and 1 in 20,000. As more families undergo TP53 testing, the true prevalence of LFS may become clearer.

Addressing Breast Cancer Risk

In the United States, National Comprehensive Cancer Network (NCCN) guidelines recommend annual breast MRI for ages 20–29 years and annual MRI and mammography from 30 to 75 years. In Australia, national guidelines recommend that bilateral mastectomy should be offered, otherwise annual breast MRI is recommended from 20 to 50 years. Schon and colleagues recommend that the option for risk-reducing bilateral mastectomy or breast screening should be considered in women without cancer with a mutation in the TP53 gene. 

NCCN Recommendations

Based on the finding that breast cancer risk increases significantly after the second decade, recommendations have included that bilateral mastectomy should be considered from age 20. The annual breast cancer risk peaks at around age 40–45 years and then decreases, such that bilateral mastectomy is less likely to benefit women over 60 years.

  • Breast awareness, starting at age 18 years, with periodic, consistent breast self-exam.
  • Clinical breast exam, every 6–12 months, starting at age 20   
  • Age 20–29 years, annual breast MRI screening with contrast
  • Age 30–75 years, annual breast MRI screening with contrast and mammogram with consideration of Tomosynthesis
  • Age >75 years, management should be considered on an individual basis.
  • For women with a TP53 mutation who are treated for breast cancer, and who have not had a bilateral mastectomy, screening with annual breast MRI and mammogram should continue as described above.
  • When the option of risk-reducing mastectomy is discussed, there should be counsel regarding degree of protection, degree of age-specific cancer risk, reconstruction options, and competing risks of other cancers. Psychosocial, social, and quality-of-life aspects of undergoing risk-reducing mastectomy should be included in such discussions.

Addressing Other Cancer Risk

NCCN Recommendations

  • Comprehensive physical exam including neurologic examination with a high index of suspicion for rare cancers and second malignancies in cancer survivors every 6–12 months.
  • Colonoscopy and upper endoscopy every 2–5 years starting at age 25 years or 5 years before the earliest known colon cancer in the family (whichever comes first).
  • Annual dermatologic examination starting at 18 years.
  • Annual whole body MRI
  • Annual brain MRI may be performed as part of the whole body MRI or as a separate exam.

Other Forms of Screening and Surveillance

There was a pilot trial of positron emission tomography (FDG-PET)/CT scans in adults with LFS that detected tumors in three of 15 individuals. These PET-CT scans, although great for finding certain tumors, also increase radiation exposure each time they are done, and so this method of scanning was halted and has shifted to whole-body MRI for adults with TP53 harmful variants.

Several research groups have begun to use an intensive screening program including rapid whole-body MRI, brain MRI, abdominal ultrasound examination, and lab tests of adrenal cortical function. This kind of surveillance program may improve survival of people with LFS by detecting tumors before there are any symptoms, but more studies are needed to show that this kind of regime works in adults and children with LFS.

Individuals with LFS have been asked about their attitudes toward cancer surveillance, and most seem to believe in the value of surveillance to detect tumors at an early stage. They also reported a sense of control and security associated with participation in a regular surveillance program

Testing Children for TP53 Mutations

It is possible to test children and adolescents for the hallmark mutations of LFS, but concerns have been raised about the potential risks, benefits, and limitations of doing so, including the lack of proven surveillance or prevention strategies, and concerns about stigmatization and discrimination.

It’s been recommended that testing individuals younger than age 18 years for TP53 pathogenic variants be done within a program that provides both pre-test and post-test information and counseling.

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