INTRODUCTION — Li-Fraumeni syndrome is an inherited autosomal dominant disorder that is manifested by a wide range of malignancies that appear at an unusually early age [1,2]. Li-Fraumeni syndrome is also known as the Sarcoma, Breast, Leukemia, and Adrenal Gland (SBLA) cancer syndrome. This cancer predisposition syndrome is inherited as an autosomal dominant disorder and is associated with abnormalities in the tumor protein p53 gene (TP53).
The molecular pathogenesis of Li-Fraumeni syndrome, its clinical manifestations, diagnosis, and management, and implications for genetic counseling of patients and their families are reviewed here. The treatment of specific malignancies that develop in these patients is discussed separately.
●(See "Chemotherapy and radiation therapy in the management of osteosarcoma".)
●(See "Rhabdomyosarcoma in childhood, adolescence, and adulthood: Treatment".)
●(See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)
●(See "Overview of the clinical features and diagnosis of brain tumors in adults".)
●(See "Treatment of adrenocortical carcinoma".)
●(See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
MOLECULAR PATHOGENESIS — The only gene that has been definitively associated with Li-Fraumeni syndrome is the tumor protein p53 gene (TP53), which is located on chromosome 17p13.1 [1-3]. Although pathogenic variants at two other locations (one at 1q23 and the checkpoint kinase 2 gene [CHEK2] locus at 22q12.1) have been postulated, there has been no validation of the 1q23 linkage, and CHEK2 has been discounted as a Li-Fraumeni gene [4]. TP53 is a tumor suppressor gene that has a major role in determining the fate of cells that contain damaged DNA. The gene product, tumor protein p53, can delay cell cycle progression, permitting an opportunity for DNA repair or initiation of programmed cell death (apoptosis). In the absence of the normal activated p53 protein, cells containing damaged DNA can survive and proliferate, which contributes to malignant transformation.
A variety of molecular techniques have been used to detect pathogenic variants in TP53, including sequence analysis of all or part of the gene, and techniques for detecting gene deletion or duplication. Over 300 distinct germline pathogenic variants of TP53 have been identified [5,6]. Pathogenic germline variants have been identified in 186 (47 percent) of the 394 codons [6]. Missense mutations comprise the majority of these; most occur in exons 5 to 8 (the DNA-binding region of the gene), with ≥35 reports each in the following codons: 337, 248, 273, 175, 245, 282, 213, and 158 [6]. It has been postulated that up to 1 in 500 people in population databases such as gnomAD carry likely pathogenic or pathogenic variants [7]. However, closer analysis of most of these variants shows that they either do not affect TP53 function or do not appear to increase cancer risk and are not associated with the Li-Fraumeni syndrome cancer pattern [8,9].
Li-Fraumeni syndrome is an autosomal dominant disease in which affected individuals have inherited one abnormal copy of TP53. In tumors from these patients, the second allele of TP53 is either somatically mutated or deleted, leaving cells with no functional gene product.
Not all patients with Li-Fraumeni syndrome diagnosed based upon clinical criteria have a detectable pathogenic variant or abnormality in TP53. The absence of a detectable pathogenic variant may be due to novel mutations that have not previously been described or to an abnormality of the gene promoter that leads to defective protein expression. Alternatively, such individuals may not have a germline abnormality in TP53, and may have a pathogenic variant in an as-yet-unidentified gene or may represent cases where the malignancy has occurred by chance. (See 'Diagnostic criteria' below.)
CLINICAL MANIFESTATIONS
Spectrum of malignancies and age at onset — The Li-Fraumeni syndrome was originally described in 1969 based upon the identification of second soft tissue sarcomas in five families with index cases of rhabdomyosarcoma [10]. These observations were subsequently extended to 24 kindreds, in which 151 individuals developed cancer [11]. These patients were characterized by a variety of bone and soft tissue sarcomas and breast cancer, approximately 80 percent of which occurred prior to 45 years of age. Other tumors that occurred disproportionately in this series included brain tumors, leukemia, and adrenocortical carcinoma, and there were six patients with cancer that was linked to antecedent radiation therapy. Other reports have confirmed the high frequency of early age at onset in patients with Li-Fraumeni syndrome, as well as the wide range of cancers that are seen [1-3,12,13].
The spectrum of malignancy and its relationship to age are illustrated by a multicenter study of 1730 patients who were referred for pathogenic variant testing based upon clinical criteria [13].
●In this cohort, 415 pathogenic variant carriers were identified, and 322 (78 percent) of the carriers had developed malignancy. Multiple primary tumors were observed in 43 percent of carriers.
●In the 132 children who had developed a malignancy, the most common tumors were osteosarcoma, adrenocortical carcinoma, central nervous system tumors (mainly glial tumors, choroid plexus carcinoma, and medulloblastoma), and soft tissue sarcoma (30, 27, 26, and 23 percent, respectively).
●In the 219 adults with malignancy, the most common were breast cancer (all in women) and soft tissue sarcoma (79 and 27 percent, respectively).
A wide variety of other malignancies have been reported in smaller numbers of patients in other series [1,13-15]. These have included melanoma, gastric cancer, lymphoma, Wilms tumor, lung adenocarcinoma, and colorectal carcinoma. As with the more common malignancies associated with Li-Fraumeni syndrome, these have also occurred at a much earlier age than that at which they commonly occur in patients without a tumor protein p53 gene (TP53) pathogenic variant.
The advent of multigene panels that include testing for TP53 is leading to an increased number of individuals diagnosed on the basis of such testing. The clinical spectrum and age at presentation may differ in populations, and at least one study suggests that such patients are significantly older at the time of cancer diagnosis and less likely to meet clinical criteria for Li-Fraumeni syndrome [16]. However, some caution over gene panel results is required. For example, some reports are erroneous due to treatment-related mutations in the bone marrow causing mosaic overgrowth of nonconstitutional TP53 pathogenic variants in clonal hematopoiesis of indeterminate potential (CHIP), affecting approximately 23 percent of positive panel results [17]. Additionally there is a risk of potential "overcalling" of non-disease-associated variants [9]; it is also possible that some germline pathogenic variants in TP53 are hypomorphic and do not give rise to the high-risk pattern of Li-Fraumeni syndrome. Nonetheless, "true" mosaic mutations in multiple tissues can account for sporadic cases with single or multiple Li-Fraumeni tumors [18]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications", section on 'Clinical use of next-generation sequencing'.)
Multiple cancers — Patients with an abnormality in TP53 who develop cancer are at a markedly increased risk of developing a second malignancy [13,19]. This was illustrated by a series of 200 Li-Fraumeni syndrome individuals from 24 kindreds who had been diagnosed with cancer [19]. In this group, 30 (15 percent) developed a second malignancy, and smaller numbers developed a third or fourth cancer. The cumulative probability of developing a second malignancy 30 years after the diagnosis of the initial cancer was 57 percent.
Radiation-associated cancers — Several case reports have suggested that radiation-induced cancers are more common in patients with Li-Fraumeni syndrome [20,21], and preclinical studies have provided additional evidence in support of this relationship [22]. Thus, radiation therapy is generally avoided as a component in the management of these patients whenever possible. (See "Radiation-associated sarcomas", section on 'Genetic predisposition'.)
Lifetime risk of cancer — There is a high penetrance of classical dominant negative pathogenic variants in TP53. For women, the lifetime risk of cancer approaches 100 percent and has been estimated to be approximately 90 percent by age 60 years [23-25]. This risk may be lower in men compared with women, with an estimated lifetime risk of developing cancer of 73 percent [26]. These risks, nonetheless, reflect pathogenic variant predominantly in the core binding domain of TP53, whereas pathogenic variant outside this region may have somewhat lower risks [27-29].
SPECIFIC MALIGNANCIES — Once cancers develop, their behavior is generally similar to that in patients without Li-Fraumeni syndrome, other than the earlier age of onset. However, the susceptibility to second and subsequent primary tumors and the implications for other family members are important factors in patient management.
Sarcomas — Almost all types of soft tissue and bone sarcomas are seen in families with Li-Fraumeni syndrome, with the exception of Ewing sarcoma. Although these tumors can occur in adults with Li-Fraumeni syndrome, the median age at onset is approximately 15 years [30]. In an analysis of 531 families or individuals with germline tumor protein p53 gene (TP53) pathogenic variant, sarcomas accounted for approximately 25 percent of tumors [31].
At all ages, osteosarcomas were more common in those with germline pathogenic variants compared with those developing sporadic sarcomas; rhabdomyosarcomas were particularly common in those less than five years of age, and embryonal-anaplastic subtype rhabdomyosarcomas in those age <5 years have an exceptionally high likelihood of having a germline TP53 variant. As an example, in observational series, pathogenic germline variants are noted at a higher frequency in patients with childhood osteosarcoma (5 to 10 percent) [32] and those with childhood rhabdomyosarcoma (6 to 23 percent) compared with those with adult sarcomas (usually ≤3 percent) [6]. (See "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis" and "Clinical presentation, histopathology, diagnostic evaluation, and staging of soft tissue sarcoma", section on 'Introduction'.)
Breast cancer — Women with Li-Fraumeni syndrome are at markedly increased risk of developing premenopausal breast cancer. In one series, the median age at diagnosis of breast cancer was 33 years [30]; in another report, approximately one-third occurred prior to age 30 years [33]. In a population-based series of breast cancer in those <31 years of age, 6 of 115 patients (5 percent) had TP53 pathogenic variants [28]. Breast cancer in men has not been a part of Li-Fraumeni syndrome.
For women with breast cancer, mastectomy, rather than lumpectomy plus radiation therapy, is generally recommended because of the risks of a second breast primary or a radiation-induced second cancer. The risk of contralateral breast cancer in TP53 carriers diagnosed at less than 35 years of age is approximately 4 to 7 percent annually, around twice that in BRCA carriers [34]. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer" and 'Radiation-associated cancers' above and "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)
Breast cancer that arises in women with a TP53 germline pathogenic variant appears to be significantly more likely to have amplification of the human epidermal growth factor receptor 2 (HER2) [27]. In a series of 12 cancers in nine young women, 10 were positive for HER2 (83 percent), whereas only 16 percent of a control group of 231 breast cancers in young women without the TP53 pathogenic variant were positive for HER2. There was no difference in the frequency of estrogen and progesterone receptor positivity. The diagnosis of a HER2-positive breast cancer in a patient before the age of 40 years can be used to help classify TP53 variants identified in panel testing [35].
Brain tumors — A wide range of brain tumors, including astrocytoma, choroid plexus carcinoma, and other infiltrative, high-grade gliomas and medulloblastoma, have been reported in patients with Li-Fraumeni syndrome, occurring either in children or young adults [30,36]. The clinical presentation, diagnosis, and management of such patients is discussed separately. (See "Treatment and prognosis of IDH-mutant astrocytomas in adults" and "Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas" and "Treatment and prognosis of medulloblastoma".)
Of particular note, a high percentage of choroid plexus carcinomas are associated with germline pathogenic variants in TP53, even in the absence of another cancer or a positive family history; some childhood series report germline pathogenic variants in approximately 40 to 69 percent of such patients [6]. (See "Uncommon brain tumors", section on 'Choroid plexus carcinoma'.)
Outside of established criteria for Li-Fraumeni syndrome, germline testing for TP53 may be indicated in those with astrocytoma and an isocitrate dehydrogenase type 1 (IDH1) R132C mutation, among others. (See "Risk factors for brain tumors", section on 'Li-Fraumeni syndrome' and "Classification and pathologic diagnosis of gliomas, glioneuronal tumors, and neuronal tumors", section on 'IDH1/IDH2 mutation'.)
Adrenocortical carcinomas — Adrenocortical carcinomas are more common in patients with Li-Fraumeni syndrome and are very frequently associated with germline pathogenic variants of TP53, both in children (46 to 93 percent) [6,30,37] and adults (4 to 14 percent) [6,12]. (See "Clinical presentation and evaluation of adrenocortical tumors" and "Treatment of adrenocortical carcinoma".)
DIAGNOSTIC CRITERIA — The diversity of tumors and the potential chance occurrence of these cancers at an early age have made establishing the diagnosis of Li-Fraumeni syndrome particularly difficult. Definitive diagnosis requires demonstration of a tumor protein p53 gene (TP53) pathogenic variant or exonic/multiexonic rearrangement (deletion or duplication).
Several different criteria have been proposed to determine which patients or families are candidates for molecular testing:
●Classical Li-Fraumeni syndrome – The original descriptions of Li-Fraumeni syndrome served as the basis for a clinical diagnosis, which was defined as follows (table 1) [3,11]:
•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
●Chompret criteria – The Chompret criteria allow the spectrum of malignancies in the proband to include sarcoma, brain tumor, breast cancer, and adrenocortical carcinoma, but they have a lower age cutoff than the classical Li-Fraumeni syndrome criteria (table 2). The Chompret criteria recommend testing for individuals with adrenocortical carcinoma, choroid plexus carcinomas, or breast cancer aged <31 years and a negative family history [13,38,39].
●Li-Fraumeni-like syndrome – The Birch definition still requires three affected individuals in the family, and the Eeles definition used slightly looser criteria to define the so-called Li-Fraumeni-like syndrome in patients who do not meet the classical Li-Fraumeni syndrome criteria [33,40]. These Li-Fraumeni-like syndrome definitions are also based upon the occurrence of typical malignancy in both the proband and one or more relatives at a relatively early age [33,40].
The classical Li-Fraumeni syndrome criteria, Chompret criteria, and Li-Fraumeni-like syndrome definitions were compared in a series of 525 cases in which samples had been referred for germline analysis for TP53 pathogenic variants [12]. Overall, pathogenic variants were identified in 91 of 525 cases (17 percent). The results of TP53 analysis were combined with clinical and family history to estimate the relative reliability of these different approaches.
Overall, the classic Li-Fraumeni syndrome criteria and the Chompret criteria were most useful [12]. When these criteria were combined, these two approaches detected 71 of 75 families with TP53 pathogenic variants (sensitivity 95 percent), with a specificity of 52 percent. The Birch and Eeles definitions of Li-Fraumeni-like syndrome each identified one additional case with a germline pathogenic variant, and in two families, none of the criteria yielded a positive result. A large Dutch study found 92 percent sensitivity for 22 of 24 pathogenic variants found in a series of 180 families [41], suggesting that testing is indicated for sarcomas and breast cancer aged <30 years without a family history.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis includes other inherited cancer syndromes in patients whose presentation suggests Li-Fraumeni syndrome.
BRCA1 and BRCA2 pathogenic variants — The hereditary breast-ovarian cancer syndrome is characterized by pathogenic variants in breast cancer gene 1 (BRCA1) or 2 (BRCA2). This syndrome is associated with a marked increase in the incidence of premenopausal breast and ovarian cancer. Other malignancies seen in individuals with BRCA2 pathogenic variants include pancreatic cancer, melanoma, and prostate cancer. (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)
A germline pathogenic variant of the tumor protein p53 gene (TP53) should be included in the differential diagnosis in young women with breast cancer who do not have a pathogenic variant in either BRCA1 or BRCA2. In a series of 161 women diagnosed with breast cancer before age 36 years and without a BRCA1 or BRCA2 pathogenic variant, sequencing TP53 revealed a characteristic deleterious pathogenic variant in 12 women (7 percent) who did not have a family history suggestive of Li-Fraumeni syndrome [38]. In 7 of the 12, there was a family history of breast cancer or a history of other malignancy suggesting Li-Fraumeni syndrome. Among the 128 patients who had no other feature suggestive of Li-Fraumeni syndrome, there were five (3 percent) with a germline TP53 pathogenic variant.
Mismatch repair cancer (Lynch) syndrome — There are a number of genes involved in the repair of DNA mismatch errors, including MLH1, MSH2, MSH6, PMS1, and PMS2. Inheritance of one abnormal allele causes hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Individuals who inherit two mutated alleles in the same mismatch repair gene have mismatch repair cancer syndrome, which is also known as Turcot syndrome. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis".)
Patients with mismatch repair deficiency syndrome are at risk for the development of leukemia, brain tumors, and intestinal cancer. Clinically, this can overlap with the spectrum seen in Li-Fraumeni syndrome, and in previously undiagnosed kindreds, patients, or families, genetic testing may be required to distinguish these syndromes. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)
MANAGEMENT — For patients with Li-Fraumeni syndrome or suspected Li-Fraumeni syndrome, key issues include who to test for pathogenic variants in the tumor protein p53 gene (TP53), the surveillance strategy for patients who have already had one or more Li-Fraumeni-associated cancers or who are known carriers of a pathogenic variant in TP53, and the optimal approach to the genetic counseling and testing of other family members.
Who to test for TP53 pathogenic variants — Testing for deleterious pathogenic variants in tumor protein p53 (TP53) can provide important information for both the tested individual and for other members of the family. The decision of whether or not to proceed with genetic testing requires careful assessment of multiple factors.
Situations where genetic counseling and TP53 pathogenic variant testing should be considered can be divided into several categories:
●Patients at high risk for Li-Fraumeni syndrome – Individuals at high risk for Li-Fraumeni syndrome based upon their clinical features (see 'Diagnostic criteria' above):
•People who satisfy either classical criteria for Li-Fraumeni syndrome (table 1) or the Chompret criteria (table 2), or who have other combinations of cancer and family history that put them at risk for Li-Fraumeni syndrome or Li-Fraumeni-like syndrome, but in whom there is no known pathogenic variant in the family. In this setting, a more extensive laboratory evaluation for pathogenic variants is required. Negative results do not rule out a diagnosis of Li-Fraumeni syndrome, and these individuals may still need to be managed as if they have Li-Fraumeni syndrome. (See 'Diagnostic criteria' above.)
•Women with early onset breast cancer (less than age 31 years) and without a detectable breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation. The index of suspicion for Li-Fraumeni syndrome is increased if there is a family history of sarcoma, brain tumor, or adrenocortical carcinoma. As with those who satisfy the classical criteria or the Chompret criteria for Li-Fraumeni syndrome, a negative result does not exclude Li-Fraumeni syndrome. Aggressive screening for cancer may be indicated for those without a detectable pathogenic variant and for those who choose not to undergo such testing. (See 'Spectrum of malignancies and age at onset' above and "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)
•Individuals with adrenocortical carcinoma, regardless of age or family history.
•Individuals with choroid plexus carcinoma, regardless of age or family history.
•Individuals with childhood sarcoma (except Ewing sarcoma), regardless of age or family history.
●Patients with a family history of a TP53 pathogenic variant – Predispositional testing may be considered for individuals from a family with a known TP53 pathogenic variant. In this setting, testing can be restricted to testing for the known pathogenic variant. A negative test in this setting effectively rules out Li-Fraumeni syndrome. Those who choose not to undergo testing should be managed as if they harbor the TP53 pathogenic variant, at least until 50 years of age; however, guidelines from the European Reference Network (ERN) on Genetic Tumor Risk Syndromes (GENTURIS) [42] do not recommend the full screening protocols outlined in the modified Toronto Protocol [43]. As surveillance is now advocated from birth for most pathogenic variants in TP53, childhood presymptomatic testing is now accepted.
●Prenatal testing – Prenatal testing may be considered for at-risk pregnancies in situations where a specific TP53 pathogenic variant has been identified.
Predisposition testing is controversial for a number of reasons [1]. Key factors to consider in deciding whether or not to conduct testing include the genetic heterogeneity associated with cancer predisposition, the fact that genetic testing only detects approximately 70 to 75 percent of individuals with Li-Fraumeni syndrome, and the psychosocial impact of a positive test. However, there is now evidence that knowledge of TP53 pathogenic variant status could alter the natural history of Li-Fraumeni-syndrome-associated cancers, and testing in early infancy can now be considered [43]. Whole-body magnetic resonance imaging (MRI) and detailed surveillance protocols detect asymptomatic tumors even in early childhood [14,42,44]. (See 'Cancer surveillance strategy' below.)
Cancer surveillance strategy — A heightened level of surveillance for cancer is required for individuals who are considered at risk, based upon a history of a Li-Fraumeni syndrome malignancy, the presence of a known TP53 pathogenic variant, or the presence of increased risk in a family with Li-Fraumeni syndrome but without an identifiable pathogenic variant or that has not undergone such testing [45]. The National Comprehensive Cancer Network (NCCN) [46], the European Reference Network (ERN) on Genetic Tumor Risk Syndromes (GENTURIS) (table 3) [42], and the American Association for Cancer Research (AACR) modified Toronto protocol [43] have defined guidelines that are useful in attempting to diagnose cancer early in patients with Li-Fraumeni syndrome.
A general overview of these guidelines are as follows (table 3):
●Childhood screening – The ERN-GENTURIS guidelines (table 3) do not advocate screening in childhood unless the TP53 pathogenic variant is known to be associated with a childhood or young adult cancer risk [42]. Children who receive screening are evaluated from birth to 18 years using physical examination, ultrasound of the abdomen and pelvis to evaluate for adrenocortical carcinoma, MRI of the brain to evaluate for brain tumors, and whole body MRI to evaluate for soft tissue and bone sarcomas.
●General assessment in adults – General measures include an annual physical examination including careful skin and neurologic examinations. Patients should be counseled to seek medical attention for evaluation of any unexplained symptoms.
•Breast cancer – Modalities available for breast cancer detection or prevention include monthly breast self-examination, clinical examination by a health care provider twice a year, and annual imaging. In general, noninvasive screening should begin around age 18 to 20 years, and diagnostic imaging should begin at age 20 to 25 years. MRI without mammography is usually preferred by most Li-Fraumeni specialists, including the author of this topic, to avoid any regular screening involving gamma irradiation [47]. While the NCCN guidelines suggest MRI and mammography (consideration of tomosynthesis) at age 30, the AACR modified "Toronto" protocol, and the United Kingdom and European (ERN-GENTURIS) guidelines (table 3) do not. Risk-reducing mastectomy may also be an option for some women.
•Colorectal cancer risk – Initiation of screening with colonoscopy at an early age (25 years) and increased frequency of screening (every two to five years) have been advocated. However, the ERN-GENTURIS guidelines (table 3) omitted colorectal screening (unless a patient had a history of abdominal radiotherapy or a family history of colorectal cancer) on the basis of poor evidence of sufficient risk, but otherwise endorsed much of the modified Toronto protocol [42,48].
•Soft tissue and bone sarcoma – On the basis of the meta-analysis, whole-body MRI on an annual basis, is recommended [43].
Multiple centers have studied the role of whole-body MRI as a surveillance strategy. A meta-analysis of 13 observational cohorts included 578 participants with germline TP53 pathogenic variants [14]. In baseline surveillance imaging, a total of 42 new cancers were diagnosed in 39 individuals (6.7 percent of the study population). Of these, 35 were localized and treated with curative intent. False-positive findings on whole-body MRI that required further evaluation (additional imaging or biopsy) were found in 173 people (29.9 percent of the cohort). The value of baseline whole-body MRI needs to be balanced against the high frequency of false-positive results. The long-term impact on outcome due to early diagnosis, and the optimal frequency of repeat scanning will require a longitudinal study.
•Brain tumors – Dedicated brain MRI is also recommended, although routine bloodwork in the absence of other abnormal assessments or cancer treatments is not warranted, according to the modified Toronto protocol [43,44].
Cancer management — The management of the various cancers is generally the same as that in patients without Li-Fraumeni syndrome. However, for women with breast cancer, mastectomy, rather than lumpectomy followed by radiation therapy, is generally preferred because of the risks of second breast cancers or radiation-induced neoplasms [19,20,49]. (See 'Breast cancer' above and 'Radiation-associated cancers' above.)
SUMMARY AND RECOMMENDATIONS
●Malignancies associated with Li-Fraumeni syndrome – Li-Fraumeni syndrome is a cancer predisposition syndrome associated with germline abnormalities of the tumor protein p53 gene (TP53). Li-Fraumeni syndrome is manifested by a tendency to develop various malignancies at an unusual age, including breast cancer, sarcomas, brain tumors, and adrenocortical carcinomas. (See 'Molecular pathogenesis' above.)
●Diagnostic criteria – Definitive diagnosis is based upon the identification of a germline TP53 pathogenic variant. The classical, Birch, and Chompret criteria have been proposed to identify individuals who are candidates for molecular screening (table 1 and table 2). (See 'Diagnostic criteria' above.)
●Approach to cancer surveillance – For individuals known to harbor a TP53 germline pathogenic variant, surveillance should include careful attention to overall health. Screening for breast cancer with magnetic resonance imaging (MRI) in women, brain tumors with MRI of the brain, and, if carried out, colon cancer with colonoscopy should begin at an early age. The use of annual whole-body MRI is now recommended (table 3). (See 'Cancer surveillance strategy' above.)
●Cancer management – The management of malignancies that are diagnosed in Li-Fraumeni syndrome patients generally is the same as for other individuals. However, in women with breast cancer, mastectomy, rather than lumpectomy plus radiation therapy, is generally indicated because of the risk of second malignancies due to radiation-induced tumors. (See 'Cancer management' above.)
