Li-Fraumeni Syndrome

Clinical characteristics.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with high risks for a diverse spectrum of childhood- and adult-onset malignancies. The lifetime risk of cancer in individuals with LFS is ≥70% for men and ≥90% for women. Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas. LFS is associated with an increased risk of several additional cancers including leukemia, lymphoma, gastrointestinal cancers, cancers of head and neck, kidney, larynx, lung, skin (e.g., melanoma), ovary, pancreas, prostate, testis, and thyroid. Individuals with LFS are at increased risk for cancer in childhood and young adulthood; survivors are at increased risk for multiple primary cancers.

Diagnosis/testing.

The diagnosis of LFS is established in a proband who meets ALL THREE classic clinical criteria and/or has a heterozygous germline pathogenic variant in TP53. Classic clinical criteria:

• A proband with a sarcoma diagnosed before age 45 years
• A first-degree relative with any cancer diagnosed before age 45 years
• A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age

Management.

Treatment of manifestations: Routine oncologic management is recommended for malignancies, with the exception of breast cancer, in which bilateral mastectomy rather than lumpectomy is recommended in order to reduce the risks of a second primary breast cancer and avoid radiation therapy. Concerns about increased risk for radiation-induced second primary tumors has led to more cautious use of therapeutic radiation in general, but most experts recommend that treatment efficacy be prioritized above concerns about late effects after careful analysis of risks and benefits.

Prevention of primary manifestations: Prophylactic bilateral mastectomy to reduce the risk for breast cancer is an option for women with a germline TP53 pathogenic variant. Colonoscopy may be considered surveillance as well as primary prevention of colorectal cancer. Avoidance of sun exposure, tobacco use, and exposure to other known or suspected carcinogens is encouraged.

Surveillance: Comprehensive physical examination and ultrasound of abdomen and pelvis every 3-4 months from birth to age 18 years, annual neurologic exam and whole-body MRI including brain MRI from the time of diagnosis. In individuals 18 years or older, complete physical exam every 6 months, ultrasound of abdomen and pelvis and dermatologic exam annually. Women should have a clinical breast examination every 6-12 months beginning at age 20-25 years, annual breast MRI beginning at age 20-30 years, annual mammogram and breast MRI from age 30 to age 75 years. Upper endoscopy and colonoscopy are recommended every 2-5 years in individuals from age 25 years.

Agents/circumstances to avoid: Minimize exposure to diagnostic and therapeutic radiation; avoid known carcinogens including sun exposure, tobacco use, occupational exposures, and excessive alcohol use.

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

Genetic counseling.

LFS is inherited in an autosomal dominant manner. Most individuals diagnosed with LFS inherited a TP53 pathogenic variant from a parent. The proportion of individuals with a de novo germline TP53 pathogenic variant is estimated to be between 7% and 20%. Offspring of an individual with an established diagnosis of LFS (i.e., an individual who meets classic LFS criteria and/or has a heterozygous germline TP53 pathogenic variant) have a 50% risk of inheriting an LFS-causative pathogenic variant and having the cancer risks associated with LFS. Predictive testing for at-risk family members, prenatal testing, and preimplantation genetic testing are possible if a TP53 germline pathogenic variant in the family has been identified.

Suggestive Findings

LFS should be suspected in individuals who meet the Chrompret criteria [Bougeard et al 2015, Valdez et al 2017], have early-onset hypodiploid acute lymphoblastic leukemia (ALL), or have suggestive findings on somatic tumor tissue testing.

• 2015 Chompret criteria (~30% will have a germline TP53 pathogenic variant) [Mai et al 2012]:
  • A proband with a tumor belonging to the LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) 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 with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history; OR
  • A female proband with breast cancer before age 31 years.
• Hypodiploid acute lymphoblastic leukemia (ALL) diagnosed in a proband <age 21 years (~50% will have a germline TP53 pathogenic variant) [Holmfeldt et al 2013]
  Note: To date, a germline TP53 pathogenic variant has not been reported in an individual with adult-onset hypodiploid ALL.
• Somatic tumor tissue testing identifies one of the following:
  • A TP53 pathogenic variant with an allele frequency of ~50% or >50%
  • Absent or decreased staining of p53 by immunohistochemistry
    Note: The LFSPRO prediction tool, based on a Mendelian model, can also be used to estimate the likelihood of identifying a germline TP53 pathogenic variant [Peng et al 2017].

Establishing the Diagnosis

The diagnosis of LFS is established in a proband who meets ALL THREE classic LFS criteria AND/OR has a germline pathogenic variant in TP53 identified by molecular genetic testing (see Table 1).

Classic LFS criteria (~60%-80% will have a germline TP53 pathogenic variant) [Mai et al 2012]:

• A proband with a sarcoma diagnosed before age 45 years
• A first-degree relative with any cancer diagnosed before age 45 years
• A first- or second-degree relative with any cancer diagnosed before age 45 years or a sarcoma diagnosed at any age

Note: Identification of low-level (<20%) mosaicism for a TP53 pathogenic variant in leukocytes is suggestive of a postzygotic (acquired) pathogenic variant due to clonal hematopoiesis of indeterminate potential (CHIP) related to aging, cytotoxic treatments, underlying hematologic malignancy or premalignancy, or circulating tumor cells [Weitzel et al 2018]. There are no standardized approaches to distinguish a TP53 pathogenic variant due to CHIP from a germline TP53 pathogenic variant, but evaluations may include the following [Weitzel et al 2018]:

• Analysis of cultured skin fibroblasts for the identified TP53 pathogenic variant
• Molecular genetic testing of all offspring to determine if the TP53 pathogenic variant was transmitted
• Molecular genetic testing of other affected family members to determine if the TP53 pathogenic variant is segregating with cancer in the family

Molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of TP53 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
• A multigene panel that includes TP53 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Multigene panels typically include additional inherited cancer genes, which are not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Li-Fraumeni syndrome (LFS) is associated with high risks for a diverse spectrum of childhood- and adult-onset malignancies. The lifetime risk of cancer in individuals with LFS is ≥70% for men and ≥90% for women [Mai et al 2016, Guha & Malkin 2017]. Five cancer types account for the majority of LFS tumors: adrenocortical carcinomas, breast cancer, central nervous system tumors, osteosarcomas, and soft-tissue sarcomas [Guha & Malkin 2017].

• Adrenocortical carcinomas (ACC) develop in 6%-13% of individuals with individuals with LFS with most diagnoses occurring before age five years. ACC also occurs in adults with LFS, typically before age 40 years [Mai et al 2016]. The southern Brazilian TP53 founder variant, p.Arg337His, is associated with a high risk of ACC, especially in childhood. In one series of individuals with pathogenic variant p.Arg337His, ACC accounted for 55% of the childhood cancers and 23% of the adult-onset cancers observed [Ferreira et al 2019]. For individuals with pathogenic variant p.Arg337His, the penetrance of childhood ACC is one in 30 to 40 [Achatz & Zambetti 2016].
• Breast cancer. Female breast cancer accounts for 27%-31% of LFS cancers, making it the most common cancer in women with LFS [Id Said et al 2016]. In one series, the cumulative incidence of breast cancer in females by age 70 was 54% [Mai et al 2016]. LFS-associated breast cancers occur at a younger age (median age: 33 years), with almost all breast cancers in women with LFS occurring prior to menopause [Bougeard et al 2015]. LFS-associated breast cancers are more likely to be ductal, estrogen receptor and progesterone receptor positive, and show HER2 amplification [Bougeard et al 2015, Mai et al 2016, Packwood et al 2019]. Malignant phyllodes tumors of the breast are also associated with LFS [Villani et al 2016]. In two series of families with LFS, no instances of male breast cancer were observed [Bougeard et al 2015, Mai et al 2016].
• Central nervous system (CNS) tumors account for 9%-14% of LFS cancers [Bougeard et al 2015]. In one series, the cumulative incidence of brain cancer by age 70 was 6% for women and 19% for men [Mai et al 2016]. The age of onset of brain tumors is biphasic with both childhood and adult onset, typically before age 40 years (median age: 16 years) [Valdez et al 2017]. Glioblastomas and astrocytomas are the most common CNS tumor types in individuals with LFS, although many other CNS tumor types have been reported, including ependymomas, choroid plexus carcinomas, and supratentorial primitive neuroectodermal tumors [Bougeard et al 2015, Valdez et al 2017]. Medulloblastomas in individuals with LFS are more likely to be of the sonic hedgehog subtype [Taylor et al 2012] and display chromothripsis (numerous clustered chromosome rearrangements occurring in malignant cells) [Zhukova et al 2013].
• Osteosarcomas account for 3%-16% of LFS cancers and typically occur prior to age 30 years (median age: 14 years), although later diagnoses up to age 55 years have been reported [Bougeard et al 2015, Mirabello et al 2015]. In one series, the cumulative incidence of bone cancers by age 70 was 5% for women and 11% for men [Mai et al 2016].
• Soft-tissue sarcomas. Rhabdomyosarcomas and other soft-tissue sarcomas are the most common LFS cancers in children and account for 17%-27% of the total cancers occurring in individuals with LFS [Bougeard et al 2015]. In one series, the cumulative incidence of soft-tissue sarcoma was 15% for women and 22% for men [Mai et al 2016]. Rhabdomyosarcomas often occur before age five years [Ognjanovic et al 2012] and are often nonalveolar tumors with diffuse anaplasia [Hettmer et al 2014].

Additional cancers. LFS is associated with an increased risk of several additional cancer types including the following:

• Leukemias and lymphomas. Primary and secondary leukemias, especially acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS) represent about 2%-4% of LFS cancers. In one series, leukemia occurred between ages two and 35 years (median age: 12 years) [Bougeard et al 2015]. ALL often exhibits a low hypodiploid state with 32-39 chromosomes [Holmfeldt et al 2013, Qian et al 2018, Swaminathan et al 2019]. Hodgkin and non-Hodgkin lymphomas account for approximately 2% of cancers reported in individuals with LFS [Bougeard et al 2015]. Lifetime risk estimates for developing leukemia or lymphoma in LFS are not established but are likely to be lower than the risks for developing any of the five most common cancers reported in individuals with LFS.
• Gastrointestinal cancers. Colorectal cancers account for about 3% of the cancers diagnosed in individuals with LFS [Guha & Malkin 2017]. A recent series reported that 8.6% of individuals with LFS were diagnosed with colorectal cancer or a polyp with high-grade dysplasia; 3.2% of these occurred before age 25 years and 4.3% before age 35 years [Rengifo-Cam et al 2018]. Additional gastrointestinal cancers have also been reported including gastric cancer [Bougeard et al 2015, Mai et al 2016]. A higher incidence of gastric cancer is reported in individuals younger than age 40 years in Asian kindreds [Ariffin et al 2015]. Lifetime risk estimates for developing gastrointestinal cancer in LFS are not established but are likely to be lower than the risks for developing any of the five most common cancers reported in individuals with LFS.
• Other cancers. Additional cancers reported in families with an identified TP53 pathogenic variant or a clinical diagnosis of LFS have included cancers of the head and neck, kidney, larynx, lung, skin (e.g., melanoma), ovary, pancreas, prostate, testis, and thyroid [Mai et al 2016, Valdez et al 2017].
• Gestational choriocarcinoma in female partners. The pregnant mother of a fetus heterozygous for a paternally inherited TP53 pathogenic variant is at risk for choriocarcinoma or another gestational trophoblastic disease (i.e., the occurrence of cancer in placental tissue, which may spread to other maternal organs) [Cotter et al 2018].

Excess of early-onset cancers. In one series, the average onset of first cancer for men with LFS was age 17 years; the average onset of first cancer for women was age 28 years when including breast cancer and age 13 years when excluding breast cancer [Bougeard et al 2015]. In another series, it was estimated that 50% of LFS-associated malignancies occurred by age 30-31 years for women and age 46 for men [Mai et al 2016].

Excess of multiple primary cancers. Individuals with LFS have a 40%-49% risk of developing a second cancer (median onset: 10 years after the first cancer diagnosis). Radiation and chemotherapy treatment of an LFS-related cancer may increase the risk for a second malignancy [Bougeard et al 2015, Churpek et al 2016, Mai et al 2016, Schon & Tischkowitz 2018].

Prognosis. In a series of 89 individuals with LFS who either selected or declined surveillance including rapid whole-body MRI, breast imaging, brain imaging, blood tests, and other targeted interventions, including upper and lower endoscopies in adults, the five-year overall survival rate was 88.8% for individuals in the surveillance group and 59.6% for those in the non-surveillance group [Villani et al 2016].

With the utilization of multigene panel testing, the number of individuals identified with a germline TP53 pathogenic variant has substantially increased. Individuals who had germline TP53 pathogenic variants identified on multigene panel testing appear to have had cancer diagnoses at older ages and less striking family histories of cancer, and were less likely to meet classic LFS or Chompret criteria compared to individuals who had a TP53 pathogenic variant identified on single-gene testing [Rana et al 2018]. Thus, there may be a broader phenotypic spectrum in LFS than was previously recognized.

Genotype-Phenotype Correlations

There continues to be debate regarding genotype-phenotype correlations in LFS.

A recent study reported that individuals with germline TP53 pathogenic variants resulting in p53 loss of function appeared to have a more severe phenotype than individuals with pathogenic variants that caused partial deficiency of p53. Individuals with loss-of-function variants had an earlier onset of first cancer, higher incidences of breast cancer before age 35 and of sarcoma, and greater likelihood of meeting classic LFS and/or Chompret criteria [Rana et al 2019].

These findings are in contrast with another series, which reported that individuals with LFS who carry dominant-negative pathogenic variants (in which the mutated p53 protein interferes with the function of the wild type p53 protein) appeared to have more clinically severe phenotypes than did individuals with other TP53 pathogenic variants [Bougeard et al 2015]. A laboratory study also reported that dominant-negative pathogenic variants appear to cause a more profound alteration of p53 DNA binding than other pathogenic variants [Zerdoumi et al 2017].

The TP53 founder variant p.Arg337His common in southern Brazil is associated with a high risk of childhood-onset ACC, up to 55% in one series [Ferreira et al 2019]. This variant is associated with an increased risk of breast cancer, as well as other LFS-associated cancers, although at older ages and with lower lifetime risks (50%-60%) compared to other TP53 pathogenic variants [Ferreira et al 2019]. Maternal inheritance of p.Arg337His was identified in 72% of individuals, suggesting preferential selection. One individual homozygous for p.Arg337His whose clinical phenotype did not appear to differ from p.Arg337His heterozygotes, has been identified [Ferreira et al 2019].

Penetrance

LFS is typically considered to be a highly penetrant cancer syndrome with a 70% or higher lifetime risk of cancer in men and a 90% or higher lifetime risk of cancer in women [Mai et al 2016, Guha & Malkin 2017]. Another study reported an 80% risk of cancer by age 70, with 22% of the cancers occurring between ages 0 and15 years, 51% between ages 16 and 50 years, and 27% between ages 51 and 80 years [Amadou et al 2018].

However, the penetrance of LFS may be overestimated as more individuals recently identified with a germline TP53 pathogenic variant do not meet classic LFS or Chompret criteria due to a less striking family and personal history of cancer [Rana et al 2018].

Individuals with TP53 pathogenic variant p.Arg337His appear to have a lower lifetime risk of cancer than those with other TP53 pathogenic variants [Ferreira et al 2019].

Genetic Modifiers

Genetic modifiers of LFS-associated cancer risk include the following:

• TP53 p.Arg72 polymorphism. The p.Arg72 polymorphism causes increased affinity toward MDM2, resulting in higher levels of p53 degradation and earlier onset of first cancer [Guha & Malkin 2017].
• MDM2 c.14+309T>G variant. The presence of the NM_002392.2:c.14+309G>T variant (also termed SNP309T>G) in the MDM2 promoter region (rs2279744) leads to increased MDM2 expression resulting in higher levels of p53 degradation and earlier onset of first cancer [Guha & Malkin 2017, Amadou et al 2018].
• microRNA R-605 variant. The presence of a variant in miR-605, which regulates the p53-MDM2 loop, resulted in a ten-year accelerated mean age of tumor onset [Guha & Malkin 2017, Amadou et al 2018].
• 16 base pair duplication polymorphism in intron 3 (PIN3). The presence of the PIN3 polymorphism appears to be protective, with older ages of first cancer compared to individuals who do not have this polymorphism [Guha & Malkin 2017, Amadou et al 2018].
• Shortened telomere length. Shortened telomere length over subsequent generations has been associated with accelerated tumor development (anticipation) in families with LFS [Guha & Malkin 2017]. The association between telomere erosion and earlier cancer onset continues to be studied.

Nomenclature

LFS was referred to as SBLA (sarcoma, breast, leukemia, and adrenal gland) syndrome in earlier publications.

Prevalence

The frequency of germline TP53 pathogenic variants in the general population is not well established. One group places the prevalence at 1:3,555 to 1:5,476 [de Andrade et al 2019].

TP53 pathogenic variant p.Arg337His is a founder variant in southern Brazil with a prevalence of 0.3% (1:375 individuals) [Achatz & Zambetti 2016, Valdez et al 2017].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Li-Fraumeni syndrome (LFS), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Due to the lifelong increased cancer risk and the diversity of tumors associated with LFS, evaluations for cancer in individuals with LFS need to be ongoing and comprehensive. Cancer monitoring can include physical examinations, blood counts, imaging studies, endoscopies, and/or biopsies (see Surveillance). Individuals with or suspected of having LFS based on clinical or molecular criteria should seek a cancer genetics consultation to review the diagnosis and medical management recommendations.

Treatment of Manifestations

In individuals with LFS, radiation therapy is avoided if possible to reduce the risk of secondary malignancies. However, treatment efficacy should be prioritized above concerns regarding risk of subsequent malignancies (e.g., radiation treatment may be necessary to provide the best chance of cure).

Women with LFS who develop breast cancer are encouraged to consider bilateral mastectomy (rather than lumpectomy) in order to reduce the risk of developing a second primary breast cancer and avoid exposure to radiation therapy [Schon & Tischkowitz 2018].

Aside from avoiding radiation therapy if possible, LFS tumors are typically treated according to standard protocols.

Prevention of Primary Manifestations

Women with LFS have the option of bilateral mastectomy to reduce the risk of breast cancer [Schon & Tischkowitz 2018].

Adults with LFS should have screening colonoscopy examinations, which can be considered surveillance as well as primary prevention of colorectal cancer [MacFarland et al 2019].

Avoidance of sun exposure, tobacco use, and exposure to other known or suspected carcinogens is encouraged.

Surveillance

Surveillance guidelines for adults and children with LFS have been developed, largely based on the "Toronto protocol" [Villani et al 2016, Kratz et al 2017, NCCN 2019].

Agents/Circumstances to Avoid

There is some evidence that TP53 pathogenic variants confer an increased sensitivity to ionizing radiation [Churpek et al 2016, Schuler et al 2017, Kasper et al 2018]. Thus, when possible, individuals with a germline TP53 pathogenic variant should avoid or minimize exposure to diagnostic and therapeutic radiation. Radiation-induced tumors and leukemias have been reported among individuals with LFS [Churpek et al 2016, Schuler et al 2017]. However, there remains limited information regarding the extent of risk posed by radiation in terms of the dosage, age of the person, or other factors [Valdez et al 2017].

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 pathogenic variants may be cumulative.

Cytotoxic chemotherapy agents may also increase the risk of treatment-related leukemias or other cancers in individuals with LFS [Churpek et al 2016, Kasper et al 2018].

Evaluation of Relatives at Risk

If a TP53 pathogenic variant has been identified in a family, molecular genetic testing of at-risk relatives can identify those family members who also have LFS and thus need increased cancer monitoring with attention to symptoms or signs of cancer and early intervention when a cancer or precancer is identified. Since the risks of LFS-related cancers are increased at all ages, including infancy and childhood, it is recommended that predictive testing be offered to individuals at birth (via cord blood analysis) or soon after birth.

If a TP53 pathogenic variant has not been identified in a family but the family meets classic criteria for LFS, all at-risk family members should be counseled regarding their potential increased risks for LFS-related cancers and options for surveillance and risk reduction.

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

Pregnancy Management

Female with LFS. Women with LFS who are pregnant should bring any potential signs or 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.

Heterozygous fetus. There are no special recommendations for screening a fetus identified as having a germline TP53 pathogenic variant. Once the infant is born, he or she should begin screening for cancer (see Surveillance).

Reproductive partner of a male with LFS. The pregnant mother of a fetus heterozygous for a paternally inherited TP53 pathogenic variant is at risk for choriocarcinoma or another gestational trophoblastic disease (i.e., the occurrence of cancer in placental tissue, which may spread to other maternal organs) [Cotter et al 2018].

Therapies Under Investigation

There are efforts to identify medications that can reduce the risk of cancer in individuals with LFS. The National Cancer Institute