Li-Fraumeni Syndrome

Li-Fraumeni Syndrome

Synonym: SBLA Syndrome (Sarcoma, Breast, Leukemia, and Adrenal Gland)

Katherine Schneider, MPH, Kristin Zelley, MS, Kim E Nichols, MD, and Judy Garber, MD, MPH.

Author Information

Initial Posting: January 19, 1999; Last Update: April 11, 2013.

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Summary

Disease characteristics. Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of the following classic tumors: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. In addition, a variety of other neoplasms may occur. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers. Age-specific cancer risks have been calculated.

Diagnosis/testing. LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline mutation in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline mutation in TP53, the only gene so far identified in which mutations are definitively associated with LFS.

Management. Treatment of manifestations: Routine oncologic management is recommended for malignancies in individuals with LFS, with the exception of breast cancer, in which mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast tumor 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 mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 mutation. Recent recommendations for colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer.

Prevention of secondary complications: Avoidance of exposure to radiation therapy, when possible, to reduce the risk of secondary radiation-induced malignancies.

Surveillance: There are no definitive prospective data on the optimal methods for and efficacy of tumor surveillance for children or adults with a germline TP53 mutation. Currently, it is recommended that: (1) children and adults undergo comprehensive annual physical examination; (2) children and adults be encouraged see a physician promptly for evaluation of lingering symptoms and illnesses; (3) women undergo breast cancer monitoring, with annual breast MRI and twice annual clinical breast examination beginning at age 20-25 years. The use of mammograms has been controversial because of radiation exposure and limited sensitivity. When included, annual mammograms should alternate with breast MRI, with one modality every six months; (4) adults consider routine screening for colorectal cancer with colonoscopy every 2-3 years beginning no later than age 25 years; (5) individuals consider organ-targeted surveillance based on the pattern of cancer observed in their family. Intensified surveillance with whole-body MRI protocols for adults and children who carry a germline TP53 mutation are being evaluated in investigational settings.

Agents/circumstances to avoid: People with germline TP53 mutations should: (1) avoid known carcinogens including sun exposure, tobacco use, occupational exposures, and excessive alcohol use; and (2) minimize exposure to diagnostic and therapeutic radiation.

Evaluation of relatives at risk: It is appropriate to offer genetic counseling and testing to all relatives who are at risk of having a familial TP53 mutation.

Genetic counseling. LFS is inherited in an autosomal dominant manner. The proportion of individuals with a de novogermline TP53 mutation is estimated to be between 7% and 20%. Offspring of an affected individual have a 50% chance of inheriting the deleterious mutation. Predisposition testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the heritable mutation in the family has been identified.

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Diagnosis

Clinical Diagnosis

Classic Li-Fraumeni syndrome (LFS) is defined by presence of all of the following criteria:

• A proband with a sarcoma diagnosed before age 45 years

• A first-degree relative with any cancer before age 45 years

• A first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age [Li et al 1988]

The diagnosis of LFS should also be suspected in individuals with the following:

• Any individual who meets the Chompret criteria for TP53 testing. It is estimated that at least 20% of individuals who meet the Chompret criteria have a detectable TP53 mutation [Chompret et al 2001]. More recent series have shown that 92%-95% of individuals who tested positive for germline TP53 mutations met the revised Chompret criteria for LFS [Gonzalez et al 2009b, Tinat et al 2009, Ruijs et al 2010]:

o Proband with a tumor belonging to the LFS tumor spectrum (e.g. soft tissue sarcoma, osteosarcoma, brain tumor, pre-menopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least one first- or second-degree relative with a LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors; OR

o 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

o Proband with adrenocortical carcinoma or choroid plexus tumor, regardless of family history

• Any woman who has a personal history of early-onset breast cancer and does not have an identifiableBRCA1 or BRCA2 mutation. A woman who is diagnosed with breast cancer before age 30 years and is not found to have a pathogenic BRCA mutation has an estimated 4%-8% likelihood of having a TP53 mutation [Gonzalez et al 2009b, Mouchawar et al 2010, McCuaig et al 2012]. Women with breast cancer diagnosed between ages 30 and 39 years may also have a small increased risk of having a TP53 mutation [Lee et al 2012].

o The likelihood of a TP53 mutation in women with early-onset breast cancer is further increased if any of the following are also present:

 A family history of cancer, especially LFS-related cancers [Tinat et al 2009, McCuaig et al 2012]

 A personal history of a breast tumor that is positive for estrogen, progesterone, and/or Her2/neu markers [Masciari et al 2012, Melhem-Bertrandt et al 2012]

 A personal history of an additional LFS-related cancer [Tinat et al 2009]

• Any individual who has a personal history of adrenocortical carcinoma (ACC), regardless of family history. The likelihood of a TP53 mutation is 50%-80% for children with ACC even in the absence of further family history [Varley et al 1999, Libé & Bertherat 2005].

o TP53 mutations may also occur in individuals with adult-onset ACC [Gonzalez et al 2009b]. In one series, 5.8% of individuals with adult-onset ACC were found to have a pathogenic TP53 mutation [Raymond et al 2013]. However, the likelihood of a TP53 mutation is lower if ACC is diagnosed in an individual older than age 40 [Herrmann et al 2012].

o Another study evaluated the correlation between somatic and germline TP53 mutations in individuals with ACC. Researchers identified aberrant p53 expression in 40% of ACC tumors. Furthermore, 25% of the individuals in the cohort with aberrant p53 expression were ultimately found to have germline TP53mutations [Waldmann et al 2012].

• Any individual who has a personal history of choroid plexus carcinoma (CPC), regardless of family history. Children with this rare type of brain tumor appear to have a high likelihood of having a TP53 mutation even in the absence of further family history.

o In one series, all nine individuals with a personal or family history of CPC had a germline TP53 mutation[Gonzalez et al 2009b].

o In another small series, 36.4% of children with CPC tested positive for a TP53 mutation [Gozali et al 2012].

Molecular Genetic Testing

Genes. TP53 is the only gene in which mutations are known to cause LFS [Malkin 2011].

About 80% of families with features of LFS have an identifiable TP53 mutation. Families who have no identifiable TP53mutations yet share certain clinical features of LFS are more likely to have a different hereditary cancer syndrome (seeDifferential Diagnosis)

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Li-Fraumeni Syndrome

Gene 1 Test Method Mutations Detected 2 Mutation Detection Frequency by Test Method 3, 4

TP53 Sequence analysis Sequence variants 5 ~95% 6, 7

Sequence analysis of select exons 8

Sequence variants 5 only in the select exons Unknown

Deletion/duplicationanalysis 9

Deletions involving the coding region, exon1, or promoter ~1% 10

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene.

4. In the approximately 80% of families with a detectable mutation

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation

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