DiagnosisClinical DiagnosisClassic LFS is defined by presence of all of the following criteria: A proband with a sarcoma diagnosed before age 45 yearsA first-degree relative with any cancer before age 45 yearsA first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age [Li et al 1988]The diagnosis of LFS should also be suspected in individuals with the following:Any individual who meets the Chompret criteria for TP53 testing. It is estimated that at least 20% of individuals who meet the Chompret criteria have a detectable TP53 mutation [Chompret et al 2001]. More recent series have shown that 92%-95% of individuals who tested positive for germline TP53 mutations met the revised Chompret criteria for LFS [Gonzalez et al 2009b, Tinat et al 2009, Ruijs et al 2010]: 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; ORProband with adrenocortical carcinoma or choroid plexus tumor, regardless of family historyAny 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]. The likelihood of a TP53 mutation in women with early-onset breast cancer is further increased if any of the following are also present:A family history of cancer, especially LFS-related cancers [Tinat et al 2009, McCuaig et al 2012]A personal history of a breast tumor that is positive for estrogen, progesterone, and/or Her2/neu markers [Masciari et al 2012, Melhem-Bertrandt et al 2012] A personal history of an additional LFS-related cancer [Tinat et al 2009]Any individual who has a personal history of adrenocortical carcinoma (ACC), regardless of family history. The likelihood of a TP53 mutation is 50%-80% for children with ACC even in the absence of further family history [Varley et al 1999, Libé & Bertherat 2005]. 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. In one series, all nine individuals with a personal or family history of CPC had a germline TP53 mutation [Gonzalez et al 2009b]. In another small series, 36.4% of children with CPC tested positive for a TP53 mutation [Gozali et al 2012]. Molecular Genetic TestingGenes. 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 SyndromeView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method ^1, 2 Test Availability TP53Sequence analysisSequence variants ^{3~95% 4, 5ClinicalSequence analysis of select exons 6Sequence variants 3 only in the select exonsUnknownDeletion/ duplication analysis 7 Deletions involving the coding region, exon 1, or promoter ~ 1% 81. The ability of the test method used to detect a mutation that is present in the indicated gene.2. In the approximately 80% of families with a detectable mutation3. Examples of mutations detected by sequence analysis may include nucleotide substitutions and/or small intragenic insertions or deletions; typically, exonic or whole-gene deletions/duplications are not detected.4. 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].5. The frequency of de novo mutations in LFS is between 7% and 20% [Gonzalez et al 2009a]. 6. Select exons may vary by laboratory.7. 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. 8. 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 resultsFor 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 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.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).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.Genetically Related (Allelic) DisordersAlthough acquired TP53 mutations are observed in numerous tumors, no other inherited phenotypes are associated specifically with germline mutations involving TP53. 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]. A recent report describes a phenotypically distinct contiguous gene deletion syndrome caused by heterozygous germline deletions that include the chromosome 17p13.1 locus, in which there is loss of TP53 as well as a number of adjacent genes. Affected individuals exhibit a common phenotype marked by developmental delay, hypotonia, and hand and foot abnormalities [Shlien et al 2010]. It is not currently clear whether individuals with these contiguous gene deletions involving the 17p13.1 locus have cancer risks similar to or lower than those with TP53 mutations.}

Natural HistoryCore 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 mutationsView in own windowTumor 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.

Differential DiagnosisTable 3. Li-Fraumeni Syndrome: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype
MIM NumberGene/LocusGene/Locus
MIM NumberLi-Fraumeni syndrome151623 TP53, P53, LFS1 191170 Li-Fraumeni syndrome609265 CHEK2, RAD53, CHK2, CDS1, LFS2 604373 Li-Fraumeni syndrome151623 CDKN2A, MTS1, P16, MLM, CMM2 600160 Li-Fraumeni syndrome 3 609266 LFS3 609266 Li-Fraumeni-like syndrome 151623 TP53, P53, LFS1 191170 Li-Fraumeni syndrome151623 TP53, P53, LFS1 191170 Data from Online Mendelian Inheritance in ManHereditary 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:A personal and family history that includes at least some of the features of LFS [Walsh et al 2006];A personal history of breast cancer diagnosed before age 30 years [Gonzalez et al 2009b].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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations 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 ManifestationsWomen 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 ManifestationsFemales 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].SurveillanceClinicians 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 AvoidThere 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 RiskOnce 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 InvestigationSearch 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. OtherThe 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].

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTP5317p13​.1Cellular tumor antigen p53IARC TP53 Mutation Database
Database of Germline p53 Mutations
TP53 @ LOVD
p53 Mutations and CancerTP53Data 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) View in own window 151623LI-FRAUMENI SYNDROME 1; LFS1 191170TUMOR PROTEIN p53; TP53Molecular Genetic PathogenesisTP53 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]. Pathologic 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 arrestApoptosisSenescenceDNA repairChanges in metabolismIn 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].