Li-Fraumeni syndrome

Other Names: Sarcoma family syndrome of Li and Fraumeni; SBLA syndrome (Sarcoma, Breast, Leukemia, and Adrenal Gland); LFS1; Li Fraumeni syndrome

Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults.

The cancers most often associated with Li-Fraumeni syndrome include breast cancer, a form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcomas. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues (leukemias), and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.

A very similar condition called Li-Fraumeni-like syndrome shares many of the features of classic Li-Fraumeni syndrome. Both conditions significantly increase the chances of developing multiple cancers beginning in childhood; however, the pattern of specific cancers seen in affected family members is different.

Epidemiology

Li-Fraumeni syndrome is thought to occur in 1 in 5,000 to 1 in 20,000 people worldwide.

Cause

Li-Fraumeni syndrome is associated with mutations in the TP53 gene. Nearly three-quarters of families with Li-Fraumeni syndrome and about one-quarter with Li-Fraumeni-like syndrome have germline mutations in the TP53 gene. Germline mutations are typically inherited and are present in essentially every cell in the body. TP53 is a tumor suppressor gene, which means that it normally helps control the growth and division of cells. Mutations in this gene can allow cells to divide in an uncontrolled way and form tumors. Other genetic and environmental factors are also likely to affect the risk of cancer in people with TP53 mutations.

A few families with cancers characteristic of Li-Fraumeni syndrome and Li-Fraumeni-like syndrome do not have TP53 mutations. The genetic factors involved in these cases are unclear.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Li-Fraumeni syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing cancer. Most people with Li-Fraumeni syndrome inherit an altered copy of the gene from an affected parent. In 7 to 20 percent of cases, however, the altered gene is the result of a new (de novo) mutation in the gene that occurred during the formation of reproductive cells (eggs or sperm) or very early in development.

For a cancer to develop in Li-Fraumeni syndrome, a mutation involving the other copy of the TP53 gene must occur in the body's cells during a person's lifetime. Cells with two altered copies of this gene do not make functional TP53 protein, which allows tumors to develop. Almost everyone who inherits one TP53 gene mutation will eventually acquire a mutation in the second copy of the gene in some cells. The second mutation often occurs in cells within the breast, bone, or muscle tissue, typically leading to the tumors common in Li-Fraumeni syndrome.

Signs and symptoms

LFS is primarily associated with sarcomas (cancers of muscle, bone or connective tissue), breast cancer, brain tumors, leukemia and adrenocortical carcinoma; however, many other types of cancer have been reported in people with this condition.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 30%-79% of people have these symptoms

• Breast carcinoma(Breast cancer)

5%-29% of people have these symptoms

• Adrenocortical carcinoma
• Astrocytoma
• Central primitive neuroectodermal tumor
• Choroid plexus carcinoma
• Colorectal polyposis
• Ependymoma
• Glioblastoma multiforme
• Osteosarcoma(Bone cell cancer)
• Rhabdomyosarcoma
• Stomach cancer

1%-4% of people have these symptoms

• Acute lymphoblastic leukemia
• Acute myeloid leukemia
• Choriocarcinoma
• Colon cancer
• Hodgkin lymphoma
• Medulloblastoma
• Melanoma
• Myelodysplasia
• Neoplasm of head and neck(Head and neck tumor)
• Neoplasm of the larynx
• Neoplasm of the lung(Lung tumor)
• Neoplasm of the pancreas(Cancer of the pancreas)
• Non-Hodgkin lymphoma
• Ovarian neoplasm(Ovarian tumor)
• Prostate cancer
• Renal neoplasm(Renal tumors)
• Testicular neoplasm(Testicular tumor)
• Thyroid carcinoma

Diagnosis

LFS should be suspected in individuals who meet the Chrompret criteria , have early-onset hypodiploid acute lymphoblastic leukemia (ALL), or have suggestive findings on somatic tumor tissue testing.

2015 Chompret criteria (~30% will have a germline TP53 pathogenic variant) :

• A proband with a tumor belonging to the LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) before age 46 years AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; OR

• A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years; OR

• A proband with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR

• A female proband with breast cancer before age 31 years.

• Hypodiploid acute lymphoblastic leukemia (ALL) diagnosed in a proband <age 21 years (~50% will have a germline TP53 pathogenic variant)

Somatic tumor tissue testing identifies one of the following:

• A TP53 pathogenic variant with an allele frequency of ~50% or >50%
• Absent or decreased staining of p53 by immunohistochemistry
• Note: The LFSPRO prediction tool, based on a Mendelian model, can also be used to estimate the likelihood of identifying a germline TP53 pathogenic variant .

Establishing the Diagnosis The diagnosis of LFS is established in a proband who meets ALL THREE classic LFS criteria AND/OR has a germline pathogenic variant in TP53 identified by molecular genetic testing.

Treatment

Routine oncologic management is recommended for malignancies, with the exception of breast cancer, in which bilateral mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast cancer and avoid radiation therapy. Concerns about increased risk for radiation-induced second primary tumors has led to more cautious use of therapeutic radiation in general, but most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits.

Prevention of primary manifestations: Prophylactic bilateral mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 pathogenic variant. Colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Avoidance of sun exposure, tobacco use, and exposure to other known or suspected carcinogens is encouraged.

NIH genetic and rare disease info

• NIH info on Li-Fraumeni syndrome

Li-Fraumeni syndrome is a rare disease.

Li-Fraumeni syndrome Resources
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