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Li-Fraumeni Syndrome

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

, MPH, , MS, , MD, and , MD, MPH.

Author Information
, MPH
Adult Oncology
Dana Farber Cancer Institute
Boston, Massachusetts
, MS
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
, MD
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
, MD, MPH
Adult Oncology
Dana Farber Cancer Institute
Boston, Massachusetts

Initial Posting: ; Last Update: April 11, 2013.

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 novo germline 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.

Diagnosis

Clinical Diagnosis

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

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]:
    • 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
    • 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
    • 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 identifiable BRCA1 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].
  • 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].
    • 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].
    • 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 TP53 mutations [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.

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 TP53 mutations yet share certain clinical features of LFS are more likely to have a different hereditary cancer syndrome (see Differential Diagnosis).

Clinical testing

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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3, 4
TP53Sequence analysisSequence variants 5~95% 6, 7
Sequence analysis of select exons 8Sequence variants 5 only in the select exonsUnknown
Deletion/duplication analysis 9 Deletions involving the coding region, exon 1, 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 of sequence analysis results, click here.

6. Sequence analysis of the entire TP53 coding region (exons 2-11) detects about 95% of TP53 mutations, most of which are missense mutations. It is estimated that about 80% of individuals with LFS have detectable TP53 mutations [Malkin 2011].

7. The frequency of de novo mutations in LFS is between 7% and 20% [Gonzalez et al 2009a].

8. Select exons may vary by laboratory.

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

10. Classic LFS can also be caused by a deletion involving the coding region of TP53 or the promoter and non-coding exon 1. Several reports of TP53 genomic rearrangements in families with LFS indicate that this type of mutation may account for about 1% of LFS cases [Bougeard et al 2003, Gonzalez et al 2009b].

Interpretation of test results

  • Duplications, inversions, large deletions, and mutations in noncoding regions are not likely to be detected by genomic sequence analysis [Bougeard et al 2003].
  • A functional assay may be useful in determining the clinical significance of novel missense mutations [Yamada et al 2009], although such testing is only performed in specific research laboratories.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of LFS is confirmed by the presence of a germline mutation in TP53.

  • Unless a specific mutation has been identified in the family, TP53 testing should be comprehensive and include both sequence and deletion/duplication analyses.

Predictive testing for at-risk asymptomatic family members requires prior identification of the pathogenic germline TP53 mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic germline TP53 mutation in the family.

Clinical Description

Natural History

Core cancers. Li-Fraumeni syndrome (LFS) is associated with high risks of a diverse spectrum of childhood- and adult-onset malignancies [Nichols et al 2001, Olivier et al 2003, Lindor et al 2008].

The tumors most closely associated with LFS are: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, and adrenocortical carcinoma. These core cancers, which are described below, account for about 70% of all LFS-related tumors [Olivier et al 2003, Gonzalez et al 2009b, Ruijs et al 2010]:

  • Sarcomas. Individuals with LFS are at increased risk of developing soft tissue and bone sarcomas. The International Agency for Research on Cancer (IARC) TP53 database found that sarcomas represented 25% of the cancers reported in people with LFS. The most commonly occurring sarcomas in the IARC TP53 database were rhabdomyosarcomas before age five years and osteosarcomas at any age. Other forms of sarcoma included leiomyosarcomas, liposarcomas, and histiosarcomas; 16 other histology types were also noted [Ognjanovic et al 2012]. LFS-related sarcomas can occur in childhood or adulthood, with most LFS-associated sarcomas occurring before age 50 years. Sarcomas that were not reported in the IARC TP53 database, and are less likely to be features of LFS, include gastrointestinal stromal tumors, desmoid tumors/fibromatosis, Ewing sarcomas, and angiosarcomas [Ognjanovic et al 2012].
  • Breast cancer. Women with LFS are at greatly increased risk of developing pre-menopausal breast cancer. The median age of breast cancer diagnosis in women with LFS is about 33 years [Olivier et al 2003]. In one series of women with LFS-related breast cancers, 32% of the cancers occurred before age 30 years and none of the breast cancers occurred after age 50 years [Birch et al 1994]. Recent data suggest that LFS-related breast cancers are predominantly positive by immunohistochemistry and FISH (for HER2/neu) for hormone receptors and/or Her2/neu [Wilson et al 2010, Masciari et al 2012, Melhem-Bertrandt et al 2012]. In one series, 84% of the LFS-related breast tumors were positive for estrogen and/or progesterone hormone markers, and 63% of the invasive breast cancers and 73% of in situ breast cancers were Her2/neu positive [Masciari et al 2012]. In another study, 67% of the LFS-related breast cancers were Her2/neu positive compared to 25% of the controls [Melhem-Bertrandt et al 2012].

    Malignant phyllodes tumors of the breast may also be associated with LFS [Birch et al 2001].

    To date, male breast cancer has rarely been reported in families with LFS.
  • Brain tumors. Individuals with LFS are at increased risk of developing many types of brain tumors (e.g., astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinomas [CPC]). LFS-related brain tumors can occur in childhood or adulthood; the median age of onset is 16 years [Olivier et al 2003].

    The likelihood of germline TP53 mutations in children with CPC is high, even in the absence of a family history suggestive of LFS [Krutilkova et al 2005, Tabori et al 2010].

    A rare peripheral nerve sheath tumor termed malignant triton tumor has also been reported in a child with a germline TP53 mutation [Chao et al 2007]. Malignant triton tumors contain schwannoma cells and rhabdomyoblasts.
  • Adrenocortical carcinomas (ACC). Individuals with LFS are at increased risk of developing ACC. Children with ACC have a 50%-80% chance of having a germline TP53 mutation, even in the absence of additional family history [Libé & Bertherat 2005, Gonzalez et al 2009b]. Individuals with adult-onset ACC may also be at increased risk for a germline TP53 mutation, especially if diagnosed before age 50 years [Gonzalez et al 2009b]. In one series, 5.8% of individuals diagnosed with ACC after age 18 years tested positive for a germline TP53 mutation [Raymond et al 2013].

Excess of early-onset cancers. Individuals with LFS are at increased risk of developing cancer at younger than typical ages. It is estimated that 50% of LFS-associated malignancies occur by age 30 years [Lustbader et al 1992]. In one series of individuals who have a germline TP53 mutation, the median age at diagnosis was 25 years [Gonzalez et al 2009b].

When assessing the likelihood that a family could have LFS, the age at diagnosis is important [Nichols et al 2001]. For example, one series found that in six individuals with germline TP53 mutations who had developed colorectal cancer, four occurred before age 21 years [Wong et al 2006]. Therefore, in assessing families with possible LFS, an unusually young age at cancer diagnosis may be as important as the specific type of malignancy observed.

Excess of multiple primary cancers. Individuals with LFS are also at increased risk of developing multiple primary tumors [Gonzalez et al 2009b]. A retrospective study on 200 affected members of families with LFS found that 15% had developed a second cancer, 4% a third cancer, and 2% a total of four cancers. In this cohort, survivors of childhood cancers were found to have the highest risks for developing additional malignancies [Hisada et al 1998]. The risk to individuals with LFS of developing a second cancer has been estimated at 57%, and the risk of a third malignancy 38%. The subsequent malignancies are not all clearly related to the treatment of the previous neoplasms.

Additional cancers. Although consensus holds that sarcomas, breast cancer, brain tumors, and ACCs constitute the core cancers of LFS, there is much less agreement about the non-core cancers which account for about 30% of malignancies in LFS.

The following malignancies have been found to occur excessively in at least some families who have met criteria for LFS and/or have tested positive for germline TP53 mutations [Chompret et al 2000, Nichols et al 2001, Olivier et al 2003, Varley 2003, Wong et al 2006, Gonzalez et al 2009b, Ruijs et al 2010]:

  • Gastrointestinal cancers. Colorectal, esophageal, pancreatic, and stomach cancers have all been reported in families with LFS. One series reported a 2.8% incidence of colorectal cancer in people with TP53 mutations with a mean age of diagnosis of 33 years [Wong et al 2006]. Another series reported that 22.6% of families with LFS had at least one relative with gastric cancer with a mean age of diagnosis of 43 years [Masciari et al 2011].
  • Genitourinary cancers. Renal cell carcinomas have been reported in families with LFS. Endometrial, ovarian, prostate and gonadal germ cell tumors have all been reported in families with LFS.
  • Leukemias and lymphomas. Leukemias, especially the acute form, were initially considered a cardinal feature of LFS; however, more recent studies have determined that leukemias are not a major feature of LFS. Hodgkin and non-Hodgkin lymphomas have also been reported in families with LFS.
  • Lung cancers – Increased risks for lung cancers have been reported in individuals with LFS, especially in those who use tobacco products [Hwang et al 2003]. A rare form of lung cancer, termed bronchoalveolar cancer, is associated with LFS [Tinat et al 2009].
  • Neuroblastomas and other childhood cancers – Children with germlineTP53 mutations may be at increased risk of developing neuroblastoma as well as other cancers of early childhood.
  • Skin cancers. Increased rates of melanoma and non-melanoma skin cancers have been reported in families with LFS.
  • Thyroid cancers. Non-medullary thyroid cancers have been reported in families with LFS.

Cancer risk. LFS is associated with high lifetime risks of cancer. The risk of cancer is estimated at 50% by age 30 years and 90% by age 60 years [Lustbader et al 1992].

Age-specific cancer rates have also been assessed. One study, based on five families with LFS, estimated age-specific cancer risks (and standard errors) as 42% (0.14) at ages 0-16 years, 38% (0.14) at ages 17-45 years, and 63% (0.27) after age 45 years; overall lifetime cancer risk was calculated at 85%. In another series, 56% of cancers in families with LFS occurred prior to age 30 years and 100% were diagnosed by age 50 years [Varley et al 1997].

The cancer risks in LFS demonstrate significant gender differences. For women with LFS, the lifetime risk of cancer is nearly 100% and for men with LFS, the lifetime risk of cancer is about 73% [Chompret et al 2000]. This gender difference in cancer risk is primarily the result of the high incidence of breast cancer among women with LFS [Chompret et al 2000, Gonzalez et al 2009b]. However, in one series, the excessive cancer risk in females with LFS was observed at all stages of life, including childhood [Hwang et al 2003, Wu et al 2006].

Ruijs and colleagues reported the following tumor-specific cancer risks based on observed versus expected cases in 24 families with LFS who had germline TP53 mutations [Ruijs et al 2010]:

Table 2. Tumor-Specific Cancer Risks in Families with LFS Who Have Germline TP53 mutations

Tumor TypeRelative Risk (95% CI)
Bone107 (49-203)
Connective Tissue61 (33-102)
Brain35 (19-60)
Pancreas7.3 (2-19)
Breast6.4 (4.3-9.3)
Colon2.8 (1-6)
Liver 1.8 (2.1-64)

Based on Ruijs et al [2010]; see p.425.

The relative risk for adrenocortical carcinoma could not be calculated in this series, because its occurrence in the general population is not known. Tumor-specific risk estimates have been difficult to establish in LFS, because of the rarity of the condition and the diverse spectrum of tumors.

Genotype-Phenotype Correlations

The following anecdotal genotype-phenotype correlations have been reported in families with LFS with germline TP53 mutations:

  • Missense mutations appear to be associated with earlier onset of cancer. In one series, the average age of tumor onset in heterozygotes for a TP53 missense mutation was eight years earlier (age 20.9 years vs 28.9 years) than for those with nonsense or other types of mutations. The authors suggest that in addition to inactivating TP53, a missense mutation may confer a separate oncogenic effect [Bougeard et al 2003, Palmero et al 2008].
  • A deletion involving all or a part of TP53 appears to confer phenotypes consistent with classic LFS [Bougeard et al 2003, Shlien et al 2010]. This contrasts with individuals with deletions extending beyond TP53, who exhibit cognitive, developmental, neurologic, and other abnormalities and may be at a lower risk for tumor formation [Shlien et al 2010].
  • The risk for brain tumors appears to be increased if the TP53 mutation lies in the DNA-binding loop that contacts the minor groove of DNA [Olivier et al 2003].
  • The risk for ACC appears to be increased if the TP53 mutation is located in the loops opposing the protein-DNA contact surface [Olivier et al 2003].
  • The TP53 mutation NP_000537.3:p.Arg337His has been found to be associated with increased risk for childhood adrenocortical carcinoma (ACC) in Brazilian studies. This mutation has also been identified in individuals with choroid plexus carcinoma, osteosarcoma, and breast cancer [Assumpcao et al 2011, Custodio et al 2011, Seidinger et al 2011, Gomes et al 2012]. Evidence suggests that p.Arg337His may be a low-penetrance allele [Achatz et al 2007, Ribeiro et al 2007, Palmero et al 2008]. However, it is important to note that the spectrum of cancers in families with the p.Arg337His mutation is beginning to resemble the pattern of cancer associated with other TP53 mutations.
  • Individuals with TP53 mutations who also have certain genetic modifiers (e.g., a specific MDM2 SNP309 allele or shortened telomere length) appear to develop cancer at earlier ages than individuals with a TP53 mutation who do not have these genetic modifiers [Bougeard et al 2003, Wu et al 2011]. This information has not yet been used extensively in clinical counseling.

There is some evidence that malignancies occur more frequently and at younger ages in families with LFS who have TP53 mutations compared to families with LFS who do not have TP53 mutations [Olivier et al 2003, Wu et al 2006, Gonzalez et al 2009b].

Penetrance

LFS is a highly penetrant cancer syndrome. The risks for cancer in LFS are estimated to be 50% by age 30 years and 90% by age 60 years [Lustbader et al 1992]. However, men with LFS may have significantly lower lifetime risks of cancer than women [Wu et al 2006] (see Clinical Description). These figures may still be somewhat biased, since individuals are typically offered TP53 testing if they are diagnosed with cancer at unusually young ages.

Anticipation

Families with LFS do appear to display genetic anticipation over successive generations.

To date, two genetic modifiers have been identified:

Another study looked at a possible generational or birth cohort effect in families with LFS, but concluded that this type of cohort effect did not adequately explain the rate of anticipation observed in families with LFS [Brown et al 2005].

Prevalence

In the past, LFS was considered to be a rare hereditary cancer syndrome. However, recent data suggest that the frequency of germline TP53 mutations may be as high as 1:5,000 to 1:20,000 [Lalloo et al 2003, Gonzalez et al 2009b]. As more families undergo TP53 testing, the true prevalence of LFS may become clearer.

Differential Diagnosis

See Li-Fraumeni Syndrome: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

Hereditary Breast-Ovarian Cancer syndrome. Families who have a predominance of pre-menopausal breast cancer are more likely to have a BRCA1 or BRCA2 mutation than aTP53 mutation [Walsh et al 2006]. Germline TP53 mutations are thought to account for fewer than 1% of total breast cancer cases [Sidransky et al 1992]. In one series, 4% of women who had breast cancer diagnosed before age 36 years and no other significant personal or family history had TP53 mutations [Tinat et al 2009].

Features of hereditary breast-ovarian cancer syndrome include cancers of the breast, ovary, pancreas, and prostate as well as melanoma. Childhood cancers are not increased among people with a single mutated BRCA1 or BRCA2 allele. The inheritance of two mutated BRCA2 alleles causes Fanconi anemia type D1.

An individual who does not have an identifiable BRCA1 or BRCA2 mutation should be offered TP53 testing if the individual has:

Constitutional mismatch repair deficiency syndrome. Children who have developed leukemia, brain tumors, or early-onset gastrointestinal cancer may have constitutional mismatch repair deficiency (CMMR-D) syndrome. CMMR-D syndrome is caused by the inheritance of two mutated alleles of a mismatch repair (MMR) gene [Tan et al 2008]. The MMR genes include: MLH1, MSH2, MSH6, PMS1, and PMS2. Inheriting one mutated allele of an MMR gene causes Hereditary nonpolyposis colorectal cancer (HNPCC), also called Lynch syndrome. Individuals with Lynch syndrome whose partners have mutations in the same MMR gene are at 25% risk of having a child with CMMR-D syndrome.

MMR genetic testing should be offered to children who have a personal history of café au lait spots and a malignancy or brain tumor plus a family history of colorectal cancer [Tan et al 2008].

In families that have features of LFS and CMMR-D syndrome, it may be appropriate to offer genetic testing for both conditions.

Germline mutations in TP53-pathway genes. Several genes in the TP53 pathway, including CHEK2 and CDKN2A, have been analyzed as possible candidate genes for LFS. At this time, TP53 is the only gene associated with LFS [Malkin 2011]. Women with CHEK2 mutations appear to be at increased risk for breast cancer. Men and women with CDKN2A mutations appear to be at increased risk for melanoma and pancreatic cancer.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

Evaluation for cancer in an individual diagnosed with Li-Fraumeni syndrome (LFS) should be based on personal medical histories and to some extent, the specific pattern of cancer in the family. Testing can include comprehensive physical examination, neurologic examination, blood counts, imaging studies, endoscopies, and/or biopsies. Individuals diagnosed with or suspected of having LFS based on molecular or clinical criteria should seek a medical genetics consultation to review the diagnosis and medical management recommendations.

Treatment of Manifestations

Women with LFS who develop breast cancer are encouraged to consider bilateral mastectomies (rather than lumpectomies) in order to reduce risks of developing a second primary breast tumor and avoid exposure to radiation therapy. However, most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits. Aside from avoiding radiation therapy, LFS-related tumors are treated according to standard protocols.

Prevention of Primary Manifestations

Females with a germline TP53 mutation have the option of prophylactic mastectomy to reduce the risk for breast cancer [Thull & Vogel 2004]. Recent recommendations for colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Counseling for avoidance of sun exposure, tobacco use, and exposure to other known or suspected carcinogens is encouraged.

Prevention of Secondary Complications

Persons with a TP53 mutation are cautioned to avoid radiation therapy whenever possible in order to limit the risk for secondary radiation-induced malignancies [Evans et al 2006]. 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. The concern regarding radiation carcinogenesis is based on older data. There is interest in examining risks associated with more modern techniques, which may be less carcinogenic.

Data on possible sensitivity to the carcinogenic effects of modern chemotherapy regimens are considerably more limited. In rare cases, individuals with germline TP53 mutations have developed myelodysplastic syndrome and/or acute myeloid leukemia after treatment with radiation or chemotherapy for a prior tumor [Hisada et al 2001, Kuribayashi et al 2005, Talwalkar et al 2010].

Surveillance

Clinicians and families need to be aware that currently no monitoring regimens have been definitively proven as beneficial for children or adults with germline TP53 mutations. Nonetheless, this is an important area of ongoing investigation.

The following is recommended:

  • Children and adults should undergo comprehensive annual physical examination including careful skin and neurologic examinations. Clinicians should be aware of the high risks for rare, early-onset cancers and also for second malignancies in cancer survivors [NCCN 2012].
  • Individuals should pay close attention to any lingering symptoms and illnesses, particularly headaches, bone pain, or abdominal discomfort. When present, the individual should see a physician promptly for evaluation [Lindor et al 2008, NCCN 2012].
  • Women should undergo breast cancer monitoring, with annual breast MRI and twice-yearly 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 [Lindor et al 2008, NCCN 2012].

The following is suggested:

  • Adults should consider routine screening for colorectal cancer with colonoscopy every two to three years beginning no later than age 25 years [NCCN 2012].
  • Individuals should consider organ-targeted surveillance based on the pattern of cancer observed in their family [NCCN 2012].

In adults with LFS, a pilot trial of screening [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scans detected tumors in three of 15 individuals. However, significant concerns were raised regarding the potential adverse consequences of the radiation exposure associated with PET/CT scans [Masciari et al 2008]. For this reason, attention has shifted to the utilization of whole-body MRI for adults with TP53 mutations.

Several groups have begun to utilize an intensive screening strategy including rapid whole-body MRI, brain MRI, abdominal ultrasound examination, and biochemical markers of adrenal cortical function. Preliminary data suggest that such a surveillance protocol may improve survival of individuals with LFS through presymptomatic detection of tumors [Villani et al 2011]. However, further prospective studies are needed to demonstrate the effectiveness of this protocol in adults and children with LFS.

Individuals with LFS have been surveyed regarding their attitudes toward cancer surveillance, given its lack of known clinical benefit. Most individuals believed in the value of surveillance to detect tumors at an early stage and also reported psychological benefits (specifically, a sense of control and security) associated with participation in a regular surveillance program [Lammens et al 2010b].

Agents/Circumstances to Avoid

There is some evidence that TP53 mutations confer an increased sensitivity to ionizing radiation [Hisada et al 1998, Varley 2003, Wang et al 2003, Cohen et al 2005]. Thus, individuals with germline TP53 mutations should avoid or minimize exposure to diagnostic and therapeutic radiation whenever possible [Varley 2003, Evans et al 2006]. Radiation-induced second malignancies have been reported among individuals with germline TP53 mutations [Hisada et al 1998, Limacher et al 2001, Cohen et al 2005]. Detailed studies to more formally assess this risk are in development.

Individuals with LFS are also encouraged to avoid or minimize exposures to known or suspected carcinogens, including sun exposure, tobacco use, occupational exposures, and excessive alcohol use, because the effects of carcinogenic exposures and germline TP53 mutations may be cumulative. For example, individuals with a germline TP53 mutation who smoke cigarettes have been shown to be at significantly increased risk of developing lung cancer than individuals with a germline TP53 mutation who do not smoke [Hwang et al 2003].

Evaluation of Relatives at Risk

Once a TP53 mutation has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial mutation and thus need increased surveillance and early intervention when a cancer is identified. However, families with LFS need to be cautioned that currently no definitive evidence demonstrates a benefit for increased surveillance or early intervention.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with LFS who are pregnant should bring any potential symptoms of cancer to the attention of their physicians. Women with LFS who are pregnant can continue to have clinical breast exams and/or breast imaging studies if indicated.

There are no special recommendations for screening a fetus identified as having a germlineTP53 mutation. Once the infant is born, he or she can be evaluated for signs of cancer.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

The Li-Fraumeni Exploration (LiFE) Research Consortium, formed in 2010, is a collaborative group of clinicians, scientists, genetic counselors, and psychologists who work with families with LFS and individuals from families with LFS [Mai et al 2012].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

LFS is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most TP53 mutations have been inherited from one of the proband’s parents.
  • If one parent has a significant personal and/or family history of cancer he/she should be tested first. Otherwise, both parents can be tested simultaneously.
  • The frequency of de novo mutations is not well established, but is estimated to be between 7% and 20% [Chompret et al 2000, Gonzalez et al 2009a].
  • Recommendations for the evaluation of parents of a child with LFS and no known family history of LFS include molecular genetic testing for the TP53 mutation found in the proband, followed by appropriate medical surveillance if either parent is identified as having the mutation.

Note: The family history may also appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

  • The risk to the proband’s siblings depends on the genetic status of the proband’s parents.
  • If one of the proband’s parents has the TP53 mutation, each sib of the proband is at 50% risk of having the mutation and cancer risks associated with LFS.
  • If neither parent has the TP53 mutation found in the proband, the proband is assumed to have a de novo mutation and the risk to sibs appears to be low. However, the risk may be slightly greater than that of the general population because of the possibility of germline mosaicism. One case of somatic de novo mosaicism has been reported in a child who developed two LFS-related malignancies [Prochazkova et al 2009].
  • If the family meets clinical criteria for LFS but the TP53 mutation cannot be identified in the proband, each sib is assumed to be at 50% risk of having LFS.

Offspring of a proband. Each child of a proband with a germline TP53 mutation is at a 50% risk of inheriting the mutation and having the cancer risks associated with LFS.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected and/or has a disease-causing mutation, his or her family members are at risk.

The specific risks of having the TP53 mutation are as follows:

  • 25% risk to second-degree relatives (grandparents, aunts, uncles, nieces, nephews, and grandchildren) (addressed above)
  • 12.5% risk to third-degree relatives (first-cousins, great-grandparents, great-aunts and great-uncles)

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When the parents of a proband with an autosomal dominant condition are genetically unaffected, it is possible that the child has a de novo mutation. Alternative explanations include variable expressivity (i.e., men with TP53 mutations may not develop cancer) and germline mosaicism. Possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Genetic cancer risk assessment and counseling. Families with LFS can present with a wide variety of medical, psychological, and familial issues [Chompret 2002, Varley 2003, Peterson et al 2008, Lammens et al 2010a].

Uptake of predisposition testing for TP53 mutations is reported to be about 40%-50%, indicating that many at-risk individuals elect not to be tested [Patenaude et al 1996, Lammens et al 2010a]. Individuals undergoing genetic testing should receive pre- and post-test genetic counseling, including discussion of the accuracy and limitations of results, the medical and psychological implications of results to individuals and their families, the logistics of testing (including cost), and potential risks and benefits of testing.

It is also important to determine motivations for the genetic counseling visit and the individual's level of understanding regarding the disorder.

Perception of cancer risk varies widely among at-risk individuals and can influence testing decisions and the impact of the test results. These perceptions of risk can be influenced by a person's previous experiences with cancer and loss, ambivalence towards testing, and the number of relatives with cancer [Peterson et al 2008].

For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute)

Cancer risk assessment modification based on age. Within families whose members have LFS, the prevalence of specific malignancies differs during childhood, adolescence, and adulthood [Olivier et al 2003]. The most common cancers observed in families with LFS per age group are:

  • 0-10 yrs. Soft tissue sarcomas, brain tumors, and ACC
  • 11-20 yrs. Bone sarcomas
  • >20 yrs. Breast cancer and brain tumors

At-risk individuals who remain cancer free into their 50s and 60s are at lower risk of having the familial TP53 mutation. However, males who did not develop childhood cancers may present in their 50s with multiple primary tumors [Wu et al 2006].

Testing of at-risk asymptomatic adults. In general, at-risk relatives should be offered genetic testing only for the specific disease-causing TP53 mutation previously identified in the family.

Molecular genetic testing of asymptomatic individuals younger than age 18 years. It is feasible to test at-risk children or adolescents for familial TP53 mutations, but the potential risks, benefits, and limitations should be carefully considered beforehand. There are legitimate concerns about testing individuals younger than age 18 years for TP53 mutations, including issues of informed consent among minors, the lack of proven surveillance or prevention strategies, and concerns about stigmatization and discrimination. Testing individuals younger than age 18 years for TP53 mutations is best performed within a program which provides both pre-test and post-test information and support. In one series, four children underwent presymptomatic TP53 mutation testing with pre- and post-test counseling before age 18 years with no negative consequences reported by the authors up to 12 years after genetic testing [Evans et al 2010]. Emerging data on screening protocols for children with LFS could alter recommendations about testing children for TP53 mutations. See Management for information on screening protocols.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Collecting a cancer history. Collecting a cancer history for a family suspected of having LFS involves obtaining information on all childhood- and adult-onset malignancies among first-, second-, and third-degree relatives. This includes information about the age of onset and the type and site of each cancer diagnosis. Obtaining written confirmation of the cancer diagnoses is important; one study found that only 55% of non-breast cancer diagnoses in families with LFS were accurately recounted [Schneider et al 2004].

Details about relatives may be incorrect or incomplete for a variety of reasons. For example, cancer may be a topic that the family avoids, or a parent's death may have led to estrangement from relatives on that side of the family. In addition, collecting a cancer history for a family with possible LFS is often emotionally charged because of the number of cancer-related illnesses and deaths among close relatives.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for families with LFS [Avigad et al 2004]. The familial TP53 mutation must be identified before prenatal testing can be performed.

Prenatal diagnosis for pregnancies at 50% risk for LFS is possible by analyzing DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some individuals in whom a TP53 mutation or a large deletion has been identified. Successful PGD has been reported for individuals with LFS [Rechitsky et al 2002, Simpson et al 2005].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Li-Fraumeni Syndrome Association
    P.O. Box 6458
    Holliston MA 01746
    Phone: 855-239-LFSA (5372)
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Coalition for Cancer Survivorship (NCCS)
    A consumer organization that advocates on behalf of all people with cancer
    1010 Wayne Avenue
    Suite 770
    Silver Spring MD 20910
    Phone: 888-650-9127 (toll-free); 301-650-9127
    Fax: 301-565-9670
    Email: info@canceradvocacy.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Li-Fraumeni Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Li-Fraumeni Syndrome (View All in OMIM)

151623LI-FRAUMENI SYNDROME 1; LFS1
191170TUMOR PROTEIN p53; TP53

Molecular Genetic Pathogenesis

TP53 has been called "the guardian of the genome" and its protein plays major roles in both the regulation of cell growth and the maintenance of homeostasis.

The loss of this important tumor suppressor gene decreases the likelihood that cells with genetic errors will be flagged for DNA repair or apoptosis. These DNA-damaged cells can go on to further proliferate, which can lead to a colony of abnormal cells and eventually a malignant tumor.

The cellular tumor antigen p53 protein plays a major role in determining whether cells undergo arrest for purposes of DNA repair or programmed cell death (apoptosis). The cellular tumor antigen p53 protein acts as a checkpoint control following DNA damage, helping delay cell cycle progression until the damaged DNA can be repaired or proceed with programmed cell death. Upon recognizing damaged DNA, the normal cellular tumor antigen p53 protein either: (1) transcriptionally activates the downstream genes (e.g., CDKN1A, MDM2, GADD45A, Bax, IGFBP1, cyclin G1, cyclin G2) to repair the DNA; or (2) directly signals a "sensor" molecule that confirms the damage and initiates apoptosis. The ability to arrest the cell cycle, a key regulatory function, occurs with proper activation of the RB pathway, which is p53 mediated. The cellular tumor antigen p53 protein may also have a direct role in the DNA repair process [Varley et al 1997].

Researchers are studying the effect of genetic modifiers on the risks for cancer in families known to have a TP53 mutation. These genetic modifiers include shortened telomere length and a specific allele in MDM2. Research on these genetic modifiers may be helpful in refining the cancer risk in families with LFS and may ultimately be important risk factors in the development of sporadic cancers as well [Lindor et al 2008].

Normal allelic variants. TP53 is a tumor suppressor gene that is 20 kilobases (kb) in genomic length with 11 exons. Exon 1 is non-coding and contains two transcriptional start sites. Alternative splicing sites are found in intron 2 and between exons 9 and 10. A transcription initiation site is present in intron 4. Two promoters have been identified: a promoter that lies upstream from TP53 and an internal promoter that lies in intron 1 [Bourdon 2007, OMIM 191170].

Pathogenic allelic variants. Nearly 300 distinct germline TP53 mutations have been described in the literature [Lindor et al 2008]. See Table A.

The majority of reported TP53 mutations are missense mutations. Most TP53 mutations have been reported within exons 5-8, which encode the core DNA-binding region of the gene. Deletions and splice site mutations have also been reported, emphasizing the need to examine both coding and non-coding regions, especially in families that meet classic LFS criteria [Bougeard et al 2003, Olivier et al 2003]. For more information, see Table A.

Normal gene product. The p53 protein is an important transcription factor. In response to cellular stress, the p53 protein becomes activated and regulates target genes to induce the following processes:

  • Cell cycle arrest
  • Apoptosis
  • Senescence
  • DNA repair
  • Changes in metabolism

In unstressed cells, the p53 protein remains inactivated primarily as a result of the presence of the MDM2 ligase [OMIM 191170].

The p53 protein has five highly conserved domains that show little variation across species. Domain I is responsible for transactivation properties, while the remaining domains (II-V) make up the core DNA-binding domain [Varley et al 1997].

Abnormal gene product. Cells that lack activated p53 protein cannot activate the appropriate chain of events when DNA is damaged. Instead, these DNA-damaged cells will be allowed to survive and proliferate, which can lead to the development of a diverse number of malignancies. Mutant p53 protein can be involved in pathways triggering gene amplification due to the impaired DNA double-stranded break repair [Sugawara et al 2011]. In addition to causing the loss of p53 protein, TP53 missense mutations may have an additional oncogenic effect [Bougeard et al 2003].

TP53 mutations may also cause increased oxidative stress to cells due to the loss of wild-type p53 function [Yoshida et al 2012]. The NP_000537.3:p.Arg337His mutation [NM_000546.5:c.1010G>A] has also been shown to confer abnormal oxidation at high physiologic pH levels [Macedo et al 2012].

References

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 1-21-13.
  2. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 11-21-13. [PMC free article: PMC1801355] [PubMed: 7485175]
  3. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 11-21-13.

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Suggested Reading

  1. The CHEK2 Breast Cancer Case-Control Consortium; CHECK2*1100delC and susceptibility to breast cancer: A collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet. 2004;74:1175–82. [PMC free article: PMC1182081] [PubMed: 15122511]
  2. Mai PL, Malkin D, Garber JE, Schiffman JD, Weitzel JN, Strong LC, Wyss O, Locke L, Means V, Achatz MI, Hainaut P, Frebourg T, Evans DG, Bleiker E, Patenaude A, Schneider K, Wilfond B, Peters JA, Hwang PM, Ford J, Tabori U, Ognjanovic S, Dennis PA, Wentzensen IM, Greene MH, Fraumeni JF, Savage SA. Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet. 2012;205:479–87. [PMC free article: PMC3593717] [PubMed: 22939227]
  3. Varley JM. Li-Fraumeni syndrome. Atlas of Genetics and Cytogenetics in Oncology and Haematology. Available online. 2000. Accessed 1121-13.

Chapter Notes

Acknowledgments

We wish to acknowledge Dr Frederick P Li for his contributions and mentorship.

Author History

Judy Garber, MD, MPH (2010-present)
Frederick P Li, MD; Dana Farber Cancer Institute (1998-2010)
Kim E Nichols, MD (2013-present)
Katherine A Schneider, MPH (1998-present)
Kristin Zelley, MS (2013-present)

Revision History

  • 11 April 2013 (me) Comprehensive update posted live
  • 9 February 2010 (me) Comprehensive update posted live
  • 12 October 2004 (me) Comprehensive update posted to live Web site
  • 3 October 2002 (me) Comprehensive update posted to live Web site
  • 19 January 1999 (me) Review posted to live Web site
  • 24 July 1998 (ks) Original submission
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