Clinical Diagnosis

Two forms of Li-Fraumeni syndrome are recognized: classic Li-Fraumeni syndrome (LFS) and Li-Fraumeni-like (LFL) syndrome.

Classic LFS is defined by the following criteria:

• A proband with a sarcoma diagnosed before age 45 years and

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

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

The 2009 Chompret criteria for LFS / TP53 testing are as follows [Tinat et al 2009]:

• A proband who has:

  • A tumor belonging to the LFS tumor spectrum (soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumor, adrenocortical carcinoma, leukemia, or lung bronchoalveolar cancer) 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 who is diagnosed with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history

LFL syndrome shares some, but not all of the features listed for LFS. Two definitions of LFL syndrome are listed below.

Birch definition of LFL syndrome [Birch et al 1994]:

• A proband 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 LFS 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

Eeles definition of LFL syndrome [Eeles 1995]:

• Two first- or second-degree relatives with LFS-related malignancies at any age

The diagnosis of LFS or LFL syndrome is confirmed by the presence of a germline mutation in TP53.

Molecular Genetic Testing

Genes. TP53 is the only gene known to be associated with LFS and LFL syndrome.

A subset of families with LFS and no identifiableTP53 mutation were initially reported to have mutations in CHEK2 [Bell et al 1999, Vahteristo et al 2001]; however, subsequent analyses determined that CHEK2 is not a major underlying cause of LFS or LFL syndrome [Evans et al 2008, Ruijs et al 2009].

A genome scan on a group of individuals with LFS who tested negative for identifiable TP53 mutations has targeted 1q23 as a locus of interest; no specific gene has been identified to date [Bachinski et al 2005].

Clinical testing

• Sequence analysis of the entire coding region. Sequence analysis of the entire TP53 coding region (exons 2-11) detects about 95% of TP53 mutations, most of which are missense mutations. A functional assay may be useful in determining the clinical significance of novel missense mutations [Yamada et al 2009]. It is estimated that 70% of individuals with LFS and 8-22% of individuals with LFL syndrome have detectable TP53 mutations [Birch et al 1994, Varley 2003]. The frequency of de novo mutations in LFS is between 7% and 20% [Gonzalez et al 2009a].

• Sequence analysis of select exons. Sequence analysis of TP53 exons 5-8 identifies about 70% of mutations. The percentage of detected mutations increases to 90% if the analysis is expanded to include exons 4-9.

• Deletion/duplication analysis. 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 classic LFS [Bougeard et al 2003, Gonzalez et al 2009b].

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

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Gene Symbol	% of LFS Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Rate by Test Method 1,2	Test Availability
TP53	70%	Sequence analysis	Sequence variants 3	~95% 4	Clinical
		Deletion/ duplication analysis 5	Deletions involving the coding region, exon 1, or promoter	~ 1%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. In the 70% of families with a detectable mutation

3. Examples of mutations detected by sequence analysis may include small intragenic

4. The mutation detection rate for sequence assay that includes exons 4 through 9

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Duplications, inversions, large deletions, and mutations in noncoding regions are not likely to be detected by sequence analysis [Bougeard et al 2003].

Testing Strategy

To confirm the diagnosis in a proband. The following individuals can be considered candidates for clinical TP53 genetic testing:

• Any individual who meets clinical criteria for LFS. It is estimated that 70% of individuals with classic LFS have a TP53 mutation detectable by sequence analysis [Varley 2003]. Testing for genomic rearrangements should be offered to individuals who meet criteria for classic LFS, but do not have a mutation detected on sequence analysis.

• Any individual who meets the Chompret criteria for LFS / 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]. In one series, 95% of individuals who tested positive for germline TP53 mutations met Chompret’s criteria or criteria for classic LFS [Gonzalez et al 2009b].

• Any individual who meets clinical criteria for LFL syndrome. The likelihood of a positive TP53 result in families with LFL syndrome is between 8% and 22% [Birch et al 1994]. The likelihood of a positive TP53 result is increased if the family history includes at least one individual with any of the following:

  • A diagnosis of cancer no later than age 40 years

  • Two or more cancer primaries

  • A diagnosis of one of the LFS “core cancers” defined as soft tissue sarcoma, osteosarcoma, premenopausal breast cancer, brain tumor, or adrenocortical carcinoma [Olivier et al 2003, Gonzalez et al 2009b]

• Any woman who has a personal history of very early onset breast cancer and does not have an identifiable BRCA1 or BRCA2 mutation. TP53 mutations account for 1% or less of total breast cancer cases [Sidransky et al 1992]. However, a woman diagnosed with breast cancer before age 30 years may have a 2%-7% likelihood of having a TP53 mutation [Lalloo et al 2006, Gonzalez et al 2009b]. A recent study assessed the frequency of TP53 mutations in a group of 161 women with breast cancer before age 36 years who had tested negative for BRCA1 and BRCA2 mutations. In this study, 4% of women with negative histories of LFS-associated malignancies had TP53 mutations compared to 16% with positive family histories and 38% with positive personal histories [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 about 80% for individuals with childhood ACC. Childhood ACC caused by de novo TP53 mutations has been reported [Varley et al 1999, Libé & Bertherat 2005]. The likelihood of identifying a TP53 mutation in individuals with adult-onset ACC is also increased, especially if diagnosed before age 50 years [Gonzalez et al 2009b].

• 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 an extremely high likelihood of having a TP53 mutation. In one series all nine individuals with a personal or family history of CPC had a germline TP53 mutation [Gonzalez et al 2009b]. De novo mutations have also been reported [Krutilkova et al 2005, Gonzalez et al 2009a].

Predispositional testing for at-risk asymptomatic family members requires prior identification of the disease-causing mutation in the family.

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

Genetically Related (Allelic) Disorders

Although acquired TP53 mutations are observed in numerous tumors, no other inherited phenotypes are associated with germline mutations. Somatic TP53 mutations are found in about 50% of all tumors, making it one of the genes most frequently altered in human cancers – and most widely studied [Meulmeester & Jochemsen 2008, Tomkova et al 2008].

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 which are 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 80% of all LFS-related tumors [Olivier et al 2003, Gonzalez et al 2009b]:

• Sarcomas. Individuals with LFS are at increased risk of developing soft tissue (i.e., muscle and connective tissue) sarcomas (e.g., rhabdomyosarcoma, liposarcoma) and sarcomas of the bone (e.g., osteosarcoma, chondrosarcoma). Almost all types of sarcomas have been noted in families with TP53 mutations with the exception of Ewing sarcoma, which is not associated with LFS. The median age of soft tissue sarcomas in individuals with LFS is 14 years and the median age of bone sarcomas is 15 years [Olivier et al 2003]. Both types of sarcoma can also occur in adulthood, with most LFS-associated sarcomas occurring before age 50 years.

• Breast cancer. Women with LFS are at greatly increased risk of developing pre-menopausal breast cancer. The median age of breast cancer 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].
  
  Malignant phyllodes tumors of the breast may also be associated with LFS [Birch et al 2001].
  
  To date, male breast cancer has not been reported in families with LFS.

• Brain tumors. Individuals with LFS are at increased risk of developing many types of brain tumors. Examples include astrocytomas, glioblastomas, medulloblastomas, and choroid plexus carcinomas (CPC). LFS-related brain tumors can occur in either childhood or adulthood; median age of onset is 16 years [Olivier et al 2003].
  
  The likelihood of germline TP53 mutations in children with choroid plexus carcinomas is high, even in the absence of additional family history [Krutilkova et al 2005].
  
  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. The median age of onset of ACC in families with LFS is three years [Olivier et al 2003]. Individuals with childhood ACC have a high likelihood of having germline TP53 mutations, even in the absence of additional family history [Libé & Bertherat 2005]. Individuals with adult-onset ACC may also have an increased risk of having germline TP53 mutations, especially if diagnosed before age 50 years [Gonzalez et al 2009b].

Excess of early-onset cancers. Individuals with LFS have increased risks for 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 TP53 mutation, the median age of diagnosis was 25 years [Gonzalez et al 2009b].

When assessing the likelihood that a family could have LFS or LFL syndrome, the age at diagnosis is important [Nichols et al 2001]. For example, one series found that in six individuals with TP53 mutations who had developed colorectal cancer four occurred before age 21 years [Wong et al 2006]. Therefore, in assessing families with possible LFS or LFL syndrome, an unusually young age at diagnosis may be as important a variable 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 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 20% of malignancies in LFS and LFL syndrome.

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

• Colorectal cancer

• Endometrial cancer

• Esophageal cancer

• Gonadal germ cell tumor

• Hematopoietic malignancies (leukemias and lymphomas)

• Lung cancer

• Melanoma and non-melanoma skin cancer

• Neuroblastoma

• Ovarian cancer

• Pancreatic cancer

• Prostate cancer

• Stomach cancer

• Thyroid cancer

• Wilms’ tumor and other kidney cancers

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%.

Cancer rates in families with LFS have also been compared to those with LFL syndrome. In one series, 56% of cancers in families with LFS occurred prior to age 30 years and 100% were diagnosed by age 50 years. In contrast, 44% of cancers in families with LFL syndrome were diagnosed before age 30 years and 78% by age 50 years [Varley et al 1997]. These findings suggest that in some families LFL syndrome may result from genetic heterogeneity and/or chance associations.

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 [Wu et al 2006].

Tumor-specific risk estimates have not been established 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 and LFL syndrome with 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 (20.9 years versus 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].

• A deletion involving the entire TP53 gene appeared to confer phenotypes consistent with classic Li-Fraumeni syndrome rather than LFL syndrome [Bougeard et al 2003].

• The risk of brain tumors seems 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 of ACC seems 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 p.Arg447His (NM_000546.4:c.1010G>A) is associated with increased risks of childhood adrenocortical carcinoma (ACC) in studies in Brazil. Questions remain as to whether the mutation is also associated with other LFS features or is a low-penetrant allele [Achatz et al 2007, Ribeiro et al 2007].

• 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]. 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 and LFL syndrome who are TP53 mutation-positive compared to families with LFS and LFL syndrome who are TP53 mutation negative [Olivier et al 2003, Wu et al 2006, Gonzalez et al 2009b].

Penetrance

LFS is a highly penetrant cancer syndrome. The risks of 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 also Clinical Description.)

Anticipation

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

To date, two genetic modifiers have been identified:

• MDM2. MDM2 is a direct negative regulator of TP53. The presence of the NM_002392.2:c.14+309G>T variant in the MDM2 promoter region (rs2279744), termed SNP309 by the authors, has been associated with the development of tumors at significantly younger ages. This accelerated rate of tumor development has been observed in families with germline TP53 mutations as well as individuals with sporadic tumors [Bond et al 2004, Bougeard et al 2006, Ruijs et al 2007].

• Telomere length. Shortened telomere length has been associated with accelerated tumor development in families with LFS [Tabori et al 2007, Trkova et al 2007]. In one series, individuals with a TP53 mutation who had childhood-onset malignancies had significantly shorter telomeres than their parents or unaffected siblings [Bougeard et al 2003].

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 1:20,000 [Gonzalez et al 2009b]. As more families undergo TP53 testing, the true prevalence of LFS may become clearer.

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.

Treatment of Manifestations

Individuals with LFS who develop breast cancer are encouraged to have mastectomies (rather than lumpectomies) in order to reduce risks of a second primary and to avoid radiation therapy. Aside from avoiding radiation therapy, LFS-related tumors are treated with routine management.

Prevention of Primary Manifestations

Females with a germline TP53 mutation have the option of prophylactic mastectomy to reduce the risk of breast cancer [Thull & Vogel 2004].

Prevention of Secondary Complications

Persons with a TP53 mutation are cautioned to avoid radiation therapy whenever possible in order to limit the risk of 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.

Data on possible sensitivity to the carcinogenic effects of modern chemotherapy regimens are considerably more limited.

Surveillance

Clinicians and families need to be aware that currently no monitoring regimens have been proven to be beneficial for children or adults with TP53 mutations.

The following is recommended:

• Children and adults should undergo comprehensive annual physical examination, which includes careful skin and neurologic examinations. Clinicians should be aware of the high risk of rare, early-onset cancers as well as the high risk of second malignancies in cancer survivors [NCCN 2008].

• Adult women should undergo breast cancer monitoring, including monthly self-breast examination and biannual clinical breast examination beginning at age 18 years; annual mammogram and annual breast MRI examination beginning at age 20-25 years or five to ten years before the earliest known breast cancer case in the family, whichever is earlier [Lindor et al 2008, NCCN 2008].

• Individuals should pay close attention to any lingering symptoms and illnesses, particularly headaches, bone pain, or abdominal discomfort and to see a physician promptly for evaluation [Lindor et al 2008, NCCN 2008].

The following is suggested:

• Adults may want to undergo screening for colorectal cancer every two to five years, beginning no later than age 25 years [NCCN 2008].

• Individuals may want to undergo organ-targeted surveillance based on the pattern of cancer observed in the family [NCCN 2008]. However, no data support the efficacy of this approach.

Several groups have begun to utilize an intensive screening strategy in children including rapid whole-body MRI, brain MRI, abdominal ultrasound examination, and biochemical markers of adrenal cortical function. Results may guide future screening recommendations.

In adults with LFS, a pilot trial of screening FDG-PET/CT scans has been reported but there are concerns about the amount of radiation exposure with the test [Masciari et al 2008]. The results of these efforts have not yet been systematically evaluated.

FDG-PET/CT scanning was explored in a small series of individuals with LFS, [Masciari et al 2008]. In this approach, whole-body FDG-PET scanning was combined with CT scanning of chest, abdomen, and areas of increased PET activity. Although tumors were detected in three of 15 individuals, significant concerns remain regarding the potential adverse consequences of the radiation exposure associated with PET/CT scans. Modifications of technique to reduce radiation exposure or replacement of CT with a non-radiation based technology are under consideration.

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 TP53 mutations should avoid or minimize exposure to radiation whenever possible [Varley 2003, Evans et al 2006]. Radiation-induced second malignancies have been reported among individuals with TP53 mutations [Hisada et al 1998, Limacher et al 2001, Cohen et al 2005].

Individuals with LFS are also encouraged to avoid or minimize exposures to other known carcinogens because the effects of carcinogenic exposures and germline TP53 mutations may be cumulative. For example, individuals with a TP53 mutation who smoke cigarettes have been shown to have significantly higher risks of developing lung cancer than individuals with a TP53 mutation who do not smoke [Hwang et al 2003].

Testing 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 need to be cautioned that there is currently no evidence demonstrating that increased surveillance or early intervention is beneficial for people with LFS.

Therapies Under Investigation

Advexin is an experimental adenoviral-based therapy that delivers wild-type TP53 to cancer cells in order to replace absent TP53, and ideally, halt cell proliferation and initiate programmed cell death (apoptosis). To date, one person with LFS with an embryonal carcinoma has been treated with Advexin and has shown an encouraging response [Senzer et al 2007, Nemunaitis & Nemunaitis 2008]. Although still in an early phase of study, the possibility of gene-based therapy that “corrects” TP53 deficient tumor cells is intriguing.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

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 established; however, in one series, four of 17 germline TP53 mutations were reported as de novo [Chompret et al 2000].

• 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 has a 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 for second-degree relatives (grandparents, aunts, uncles, nieces, nephews, and grandchildren) (addressed above)

• 12.5% for third-degree relatives (first-cousins, great-grandparents, great-aunts and great-uncles)

Related Genetic Counseling Issues

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 or LFL syndrome can present with a wide variety of medical, psychological, and familial issues [Chompret 2002, Varley 2003, Peterson et al 2008].

Uptake of predisposition testing for TP53 mutations in one research program was only 39%, indicating that many at-risk individuals elect not to be tested [Patenaude et al 1996]. 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.

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. Such testing is available clinically (see Molecular Genetic Testing).

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 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 18 years for TP53 mutations is best performed within a program which provides both pre-test and post-test information and support. Emerging data on screening protocols for children with LFS could alter recommendations about testing children for TP53 mutations.

See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics (1995) 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 or LFL syndrome 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.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

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

Prenatal diagnosis for pregnancies at 50% risk of LFS or LFL syndrome 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 available for families in which the disease-causing mutation has been identified in an affected family member. Successful preimplantation genetic diagnosis has been reported for families with LFS or LFL syndrome [Rechitsky et al 2002, Simpson et al 2005]. For laboratories offering PGD, see .

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 of 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].

Published Guidelines/Consensus Statements

1. The National Society of Genetic Counselors (1997) Statement regarding genetic testing for adult-onset disorders .
2. The American Society of Human Genetics/American College of Medical Genetics (1995) Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.
3. American Society of Clinical Oncology (2003) Policy statement update: Genetic testing for cancer susceptibility .

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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. Varley JM (2000) Li-Fraumeni syndrome. Available online at Atlas of Genetics and Cytogenetics in Oncology and Haematology. atlasgenetics.oncology.org.

Author History

Judy Garber, MD, MPH (2010-present)
Frederick P Li, MD; Dana Farber Cancer Institute (1998-2010)
Katherine A Schneider, MPH (1998-present)

Acknowledgments

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

Revision History

• 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