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s12672-024-01435-w
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Review
Abstract
Li-Fraumeni syndrome is a rare yet serious hereditary cancer predisposition syndrome, marked by a significant early-
life increased risk of developing cancer. Primarily caused by germline mutations in the TP53 tumor suppressor gene,
Li-Fraumeni syndrome is associated with a wide range of malignancies. Clinical management of Li-Fraumeni syndrome
could be challenging, especially the lifelong surveillance and follow-up of patients which requires a multidisciplinary
approach. Emerging insights into the molecular and clinical basis of Li-Fraumeni syndrome, coupled with advances in
genomic technologies and targeted therapies, offer promise in optimizing risk assessment, early detection, and treatment
strategies tailored to the unique clinical and molecular profiles of affected individuals. This review discusses Li-Fraumeni
syndrome in more depth, reviewing molecular, genomic, epidemiological, clinical, and therapeutic aspects of this disease.
Keywords Adolescents and young adults cancer · AYA· Cancer predisposition syndromes · Hereditary cancer ·
Li-Fraumeni · p53 · TP53
1 Background
Li-Fraumeni syndrome (LFS), also addressed as the “Sarcoma, Breast, Leukemia, and Adrenal Gland” (SBLA) syndrome, is
a rare autosomal dominant cancer predisposition syndrome [1]. First described over fifty years ago, the initial suspicion
was raised by Frederick P. Li and Joseph F. Fraumeni as an “increased familial susceptibility to cancer” was observed “not
only by the large number of members affected but by a seeming excess of multiple primary neoplasms”, suggesting a
potentially familial origin of the observed malignancies [2, 3]. The diagnosis of LFS is challenging due to its heterogene-
ous clinical presentation and diagnostic controversies [4, 5]. Moreover, the surveillance of LFS patients poses a further
challenge to clinicians, as the individuals commonly face recurrent states of malignancies, either due to genetic pre-
disposition or complications of previous cancer treatments [6, 7]. This review aims to provide comprehensive basic and
clinical insight into LSF, discussing this syndrome’s genomic, epidemiological, and clinical aspects.
* Mohammad‑Salar Hosseini, [email protected]; [email protected] | 1Research Center for Integrative Medicine in Aging,
Aging Research Institute, Tabriz University of Medical Sciences, Golgasht Street, Tabriz 51666, EA, Iran. 2Hematology and Oncology
Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 3Research Center for Evidence‑Based Medicine, Iranian EBM Center:
A JBI Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran.
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2 Main text
LFS is primarily associated with germline mutations in the TP53 gene, located on chromosome 17p13 [8, 9]. TP53 encodes
the p53 protein, a critical tumor suppressor involved in regulating cell cycle progression, DNA repair, apoptosis, and
senescence, with its alterations widely contribute to cancer development [10, 11]. The loss of the tumor suppressor func-
tion results in impaired cell cycle regulation, uncontrolled cell proliferation, increased genomic instability, and ultimately,
predisposes the affected individuals to cancer development [12–14]. Therefore, TP53 holds fundamental regulatory roles
in maintaining cellular responses to stressors, including DNA damage, hypoxia, and oxidative stress, thereby safeguarding
genomic integrity [15, 16]. Figure 1 demonstrates the impact of TP53 mutation in terms of genomic and cellular pathways.
The spectrum of TP53 mutations linked to LFS includes various molecular abnormalities, including missense muta-
tions, frameshift mutations, in-frame mutations, splice site mutations, and nonsense mutations [17, 18]. As the most
common mutations in this case, missense mutations result in the amino acid sequence alterations in the p53 protein,
compromising its structural integrity and functional competence (Fig. 2). Nonsense mutations cause the p53 protein to
prematurely truncate, eliminating its tumor suppressor properties and precipitating the onset of an aggressive neoplastic
phenotype. Comparably, frameshift mutations disrupt the reading frame of TP53, resulting in aberrant protein translation
and functional incapacitation, while splice site mutations interrupt the fidelity of RNA splicing, thereby engendering
diverse phenotypic outcomes, depending on the resulting transcript variants [19, 20].
The nucleotide mutation patterns are dominantly C-to-T transitions at CpG dinucleotides, prone to methylation and
subsequent deamination, making them hotspots for mutations [21]. Other substitutions, such as G-to-A or A-to-G tran-
sitions, occur less frequently and tend to have varying impacts on p53’s function [22]. Figures 2 and 3 exhibit the distri-
bution of TP53 mutation variants and mutation effects, highlighting the non-random nature of TP53 mutations, with a
marked preference for specific types of transitions and transversions.
Although mutations have been detected in almost every codon, the majority of pathogenic TP53 mutations occur
within exons 5 to 8 in the DNA-binding domain (around codons 100 to 300), which is crucial for the protein’s ability to
mediate tumor suppression [21, 23, 24]. Mutations in the transactivation domain are less common but can disrupt the
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Fig. 3 TP53 mutation variant distribution based on the mutation patterns (N = 28,866 – data from TP53 Database, R20)
pro-apoptotic abilities of p53 [25, 26]. Mutations can also occur in the oligomerization domain (exons 9 and 10), often
impairing the structural integrity and stability [17, 27]. Codons 175, 245, 248, 273, and 282 are among the most com-
mon hotspot mutations [21, 23]. Additionally, specific founder variants of TP53 have also been observed in particular
populations, such as R337H and P47S, which are more prevalent among Brazilians and individuals of African descent,
respectively, both affecting non-DNA-binding domains [28, 29]. R337H mutation has contributed to a high incidence of
adrenocortical carcinoma (ACC), but is notable for its incomplete penetrance [30]. Moreover, Some missense mutations
in TP53 have a dominant-negative effect, meaning the mutant p53 protein not only loses its tumor-suppressive function
but also interferes with the function of the remaining wild-type p53, exacerbating the cancer risk [31]. Hotspot mutations
such as R175H, R248Q, and R273H are examples of dominant-negative mutations [32, 33].
Considering the higher prevalence of hotspot mutations, the profound impact of dominant-negative mutations, and
the co-prevalence of founder variations with specific cancer types, recent studies and secondary analyses have focused
on potential genotype–phenotype correlations [34, 35]. Although the hotspot variations show a likely shift toward
early-onset (before 31) breast cancer and sarcoma, current evidence is inconclusive for any significant correlations [36].
There is still significant variability in how TP53 mutations manifest clinically. Even within families, individuals with the
same TP53 mutation can present with different malignancies, different onset ages, and varying treatment responses [37].
2.2 Epidemiology
Studies have shown that LFS is a rare hereditary cancer predisposition syndrome with an estimated prevalence ranging
from 1 in 5,000 to 1 in 20,000 individuals in the general population [38]. Geographically, LFS exhibits global distribution
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without remarkable ethnic or racial preferences, although certain populations may exhibit founder mutations or higher
prevalence rates attributable to genetic drift, population bottlenecks, or consanguinity [39, 40]. Despite its rarity, LFS
exhibits considerable variability in penetrance and expressivity, with inter-individual variability in tumor spectrum, age
of onset, and disease trajectory, attributable to modifier genes, environmental influences, and stochastic and random
events [41–44].
The general viewpoint on LFS suggests a high penetrance of this familial syndrome, with about 80% risk of can-
cer during the individual’s lifespan [45, 46]. Studies estimate that over 350,000 individuals have germline TP53 muta-
tions—substantially more than registered cases—suggesting either a potential underdiagnosis of LFS cases worldwide
or variation in its estimated penetrance [47, 48]. Also, there have been several reports of individuals with rare early-onset
malignancies and TP53 mutations who have had a negative familial history of cancer, suggesting a potentially higher
prevalence of LFS than estimated [49–52].
Tables 1 and 2 present the tumor site distribution of TP53 germline mutations in confirmed carriers and mutations
identified in human tumor samples, retrieved from the R20 release of TP53 database [53, 54]. As presented, breasts, soft
tissues, brain, adrenal glands, and bones are the most common tumor sites in individuals with TP53 germline mutations.
Around half of the TP53 mutation carriers are expected to develop cancer before the age of 30 [55, 56]. Notably,
the prevalence of LFS may be underestimated due to challenges in clinical detection, diagnostic ascertainment, and
genetic testing accessibility [57, 58]. The advent of next-generation sequencing (NGS) technologies and expanding
indications for genetic testing in oncology practice have facilitated the identification of novel germline TP53 mutations
and expanded the clinical spectrum of LFS-associated malignancies beyond the classic triad of sarcomas, breast cancer,
and brain tumors [59, 60].
2.3 Clinical features
LFS is characterized by a diverse spectrum of malignancies affecting multiple organ systems. Common tumors associ-
ated with LFS include soft tissue sarcomas, breast cancer, brain tumors (such as glioblastoma and medulloblastoma),
adrenocortical carcinoma, and leukemia, particularly, acute lymphoblastic leukemia (ALL) [61, 62]. The age of onset for
cancer in LFS is typically younger compared to the sporadic cases, with many tumors diagnosed during childhood or
early adulthood [20]. Additionally, individuals with LFS are at increased risk of developing multiple primary cancers over
their lifetime, further complicating management and surveillance strategies [63].
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2.3.1 Sarcoma
Sarcomas are a hallmark presentation of LFS, constituting a significant proportion of malignancies encountered
in affected individuals. Sarcomas contribute to one-fourth of all tumors in LFS patients, with the majority of cases
exhibiting before 50 years old [64].
The mesenchymal tumors arise from connective tissues, including but not limited to bones, cartilage, muscle, adi-
pose tissue, and blood vessels, in different locations such as extremities, retroperitoneum, and head and neck regions,
resulting in malignancies such as osteosarcoma [65], Ewing sarcoma [66], chondrosarcoma [67], rhabdomyosarcoma
[68], leiomyosarcoma [69], liposarcoma [70], angiosarcoma [71], malignant peripheral nerve sheath tumors (MPNSTs)
[72], and gastrointestinal stromal tumors (GISTs) [73]. Sarcomas generally vary in histologic subtypes, and could be
accompanied by diverse clinical presentations and therapeutic responses.
LFS-related sarcomas usually develop in childhood or early adulthood, often preceding the diagnosis of other
LFS-associated malignancies. The clinical presentations of sarcomas in LFS are characterized by their heterogeneity
and tendency for metastasis and dissemination through the body [74]; therefore, any clinical suspicion is typically
followed by comprehensive imaging studies and histopathological evaluations [75]. Rhabdomyosarcoma and osteo-
sarcoma are among the most common sarcoma subtypes encountered in LFS [8].
2.3.2 Breast cancer
In addition to sarcomas, LFS patients are at a significantly greater risk of breast cancer. In fact, breast cancer is the
most prevalent cancer in female patients with LFS [76]. Previous studies have indicated that women with LFS experi-
ence breast cancer almost three decades earlier than the general population, usually with a mean onset age of around
32–38 [76–79]. Studies have suggested the potential impact of reproductive factors since significant protective effects
of breastfeeding for over seven months have been observed in respective populations [80].
Breast cancer in the context of LFS often exhibits aggressive histopathological features, including high histologic
grade and overexpression of HER2/neu oncogene, tending towards an inferior overall survival compared to spo-
radic cases [77, 81]. Many LFS cases of breast cancer are estrogen receptor (ER) and human epidermal growth factor
receptor 2 (HER2)-positive, suggesting the potential association of early-onset HER2-positive breast cancer with the
presence of TP53 mutations [82].
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Clinical presentations of breast cancer are diverse and could be the earliest presenting signs and symptoms of LFS.
Notably, breast cancers in LFS frequently emerge at a younger age compared to sporadic cases, making early breast
cancer an alarming sign for clinicians to initiate an in-depth workup for LFS [56, 76, 83].
2.3.3 Brain tumors
Central nervous system (CNS) tumors could range from high-grade gliomas, namely glioblastoma multiforme, to embryo-
nal tumors, such as medulloblastoma, with variable histologic subtypes and clinical behaviors [84, 85]. These CNS tumors
may present with neurological symptoms, including headaches, seizures, focal deficits, and merely cognitive impairments,
prompting diagnostic evaluation with further neuroimaging modalities [86].
Glioma, including astrocytoma, oligodendroglioma, and glioblastoma, along with medulloblastoma and choroid
plexus carcinoma, are the most common subtypes of brain cancer associated with LFS [85, 87–89]. Glioma exhibits infil-
trative growth patterns and aggressive histologic features, commonly with therapeutic resistance [90, 91]. Medulloblas-
toma is another LFS-associated brain tumor arising from the cerebellum, characterized by the propensity for metastatic
dissemination via cerebrospinal fluid (CSF) [92].
2.3.4 Adrenocortical carcinoma
On the other hand, ACC could present with nonspecific or constitutional symptoms such as abdominal pain. Although
ACC cases are generally sporadic, further evaluation for genetic predispositions such as LFS or multiple endocrine neo-
plasia (MEN) syndrome is recommended upon diagnosis [93].
Arising from the adrenal cortex, ACC usually presents with an aggressive clinical course, propensity for metastatic
spread, and poor prognosis [94]. The clinical presentations of ACC in LFS are variable and nonspecific, often mimick-
ing symptoms of other adrenal disorders, including Cushing’s syndrome, or constitutional symptoms such as fatigue,
weight loss, and abdominal fullness [95]. Notably, ACC may also be accidentally detected in imaging studies performed
for unrelated indications, or during treatment for other diagnoses [96].
2.3.5 Hematologic malignancies
Hematologic malignancies might not be the initial denoting manifestation of LFS, but, in the case, they could present
with unspecific or constitutional symptoms, along with splenomegaly, lymphadenopathy, or blood count abnormalities
in further clinical evaluation and workup [97]. Although LFS accounts for less than 1% of ALL cases—the most frequently
reported LFS-linked leukemia—in children, it comes with a significant predisposition to adverse treatment outcomes
and second cancers [97, 98]. Furthermore, studies have reported an estimated six times higher risk of developing leu-
kemia in the LFS population [99]. Acute myeloid leukemia (AML), myelodysplastic syndromes, and lymphomas are also
linked to LFS, but present with lower incidence [100]. TP53 mutation and LFS are linked to 10–15% and 5% of AML cases,
respectively [101].
As a consequence of dysregulated proliferation and differentiation of hematopoietic precursors, culminating in the
emergence of abnormal hematopoietic clones with malignant potential, hematologic malignancies often display aggres-
sive clinical behaviors in LFS patients, with resistance to conventional therapies, relapse, and propensity for recurrence
[102–105].
2.3.6 Other presentations
Not all cases of LFS typically present with the discussed presentations, as many LFS cases have been reported with other
malignancies. For instance, some studies have indicated melanoma as a potentially LFS-related malignancy; however,
the association between LFS and melanoma is currently indefinite [106–108].
Figure 4 displays the most common tumor sites and clinical presentations of LFS.
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Fig. 4 The most common malignancies of Li-Fraumeni syndrome, along with their most common clinical presentations
2.4 Diagnosis
The diagnosis of LFS should be based on a combined clinical and genetic approach. Nonetheless, the definite diagnosis
of LFS relies on TP53 mutation. However, several diagnostic criteria have been introduced to help clinicians effectively
diagnose LFS and Li-Fraumeni-like syndrome (LFLS) cases, including the classic criteria, Chompret and its updated cri-
teria, the Birch criteria, and the Eeles criteria [110–113]. Table 3 summarizes the proposed criteria for both LFS and LFLS.
The classic criteria for LFS include:
Individuals meeting the clinical criteria are referred to genetic testing for TP53 mutations. In addition to genetic test-
ing, comprehensive familial pedigree analysis plays a vital role in clarifying the hereditary basis of cancer predisposition
syndromes, including LFS. Patients with other combinations for personal or familial history of malignancies could still
be considered clinically high-risk for LFS and managed accordingly. Importantly, in cases of high clinical suspicion, a
negative result for the detectable pathogenic variants does not exclude the LFS diagnosis [114].
The National Comprehensive Cancer Network (NCCN) recommends testing for individuals complying with CRIT-7
(testing criteria for LFS), including individuals fulfilling classic LFS or Chompret criteria, individuals with personal/famil-
ial history of pediatric hypodiploid ALL, and people with cancer with a pathogenic/likely pathogenic (P/LP) TP53 vari-
ant identified on tumor-only genomic testing, with germline evaluation considered in patients with an age of cancer
diagnosis before 30 years old, or per clinician discretion [115]. However, in case the criteria are unmet, testing for other
hereditary syndromes should be considered.
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Table 3 Diagnostic criteria for Li-Fraumeni syndrome, requiring further screening for germline TP53 mutation
Disease Diagnostic criteria Description
Considering the high risk of developing cancer at a young age, individuals with LFS require lifelong surveillance and
screening to detect tumors at an early, potentially curable stage. The preferred screening modalities and intervals
should be based on the treating physicians’ discretion. Although there are controversies among current surveillance
protocols, some routine screenings are recommended in most guidelines, including [109, 114, 116, 117]:
Table 4 compares LFS surveillance protocols from the latest guidelines and consensuses in more detail [109,
114–118]. Recent studies have also proposed novel cell-free DNA (cfDNA) approaches toward early cancer detection
in LFS patients [119].
Routine clinical examination is necessary for LFS patients [120]. Starting from basic vital signs, clinicians should
look after any indicating symptoms and signs, including pallor, unexplained weight loss, Cushing’s-like facial features,
night sweet, persistent or progressive pain, sense of lump, bulge, or swelling, headache, seizure, visual disturbance in
any form, hemoptysis, chest pain, shortness of breath, or any skin changes. The management of LFS requires a multi-
disciplinary approach, involving genetic counseling, cancer surveillance, risk reduction strategies, and personalized
treatment interventions. Lifestyle modifications should be made to reduce cancer risk, including smoking cessation
and maintaining a healthy weight [121].
Clinicians should consider that patients with TP53 mutations with a history of previous malignancy are prone to the
development of a second cancer [122]. Radiation-induced malignancies are one of the more prevalent malignancies
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Table 4 Surveillance protocols based on the latest guidelines and recommendations
Surveillance Toronto Protocol (2016) [116] NCCN (2024) [115] AACR (2017) [117] GENTURIS (2020) [109] SEOM & AEGH (2020) [118] Japanese LFS Expert Group
Component (2021) [114]
Adreno- From birth to - Abdominopel- Beginning in - US, q 3-4 m From birth - Abdomin- From birth to - Abdominal From birth to - Abdomin- From birth to - Abdominopel-
cortical 40y vic US, q 3-4 m infancy (to 18y) opelvic US, q 18y US, q 6 m 18y opelvic US, q 17y vic US, q 3-4 m
carcinoma - Blood testsa, q 3-4 m - Urine steroids 3-6 m - Blood tests (if
3-4 m - Blood testsb (if US not - Blood testsb US impossi-
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Table 4 (continued)
Surveillance Toronto Protocol (2016) [116] NCCN (2024) [115] AACR (2017) [117] GENTURIS (2020) [109] SEOM & AEGH (2020) [118] Japanese LFS Expert Group
Review
Gastrointesti- From 25yl - Colonoscopy, From 25ym - Colonoscopy and From 25y - Upper endos- From 18y - Colonoscopy From 18y - Colonoscopy From 25y - Upper and
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nal cancer onwards q 2y onwards upper endoscopy, onwards copy and onwards (only in case onwards (in cases of onwards lower GI
q 2-5y colonoscopy, of previous previous endoscopy, q
- Patients with prior q 2-5y abdominal abdominal 2-5y
whole body/ cancer RT RT or family
abdominal RT: or familial history of
colonoscopy is history of colorectal
recommended 5y colorectal cancer), q 5y
after treatment cancer), q 5y
Soft tissue From birth to - Whole-body Beginning in - Whole-body MRI From birth to - Whole-body From birth to - Whole-body From birth - Whole-body From birth to - Whole-body
and bone 18y MRI, q 1y infancy q, 1y 18y MRI q, 1y 18y MRI (without MRI without 17y MRI q 1yn
sarcoma gadolinium gadolinium
enhance- enhance-
ment) for ment, q 1y
high-risk
TP53
variantse
or patients
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with prior
chemo-
therapy/RT,
q 1y
From 18y - Whole-body From 18y - Whole-body From 18y - Whole-body From 18y - Whole-body
onwards MRI, q 1y onwards MRI q, 1yk onwards MRI, q 1y onwards MRI, q 1
yk,n
- Abdominopel- - Abdomin- - Abdominopel-
vic US, q 3-4 m opelvic US, vic US, q 1y
(2024) 15:561
q 1y
Melanoma From 18y - Dermatological From 18y - Dermatological From 18y - Dermatologi- – – – – From 18y - Dermatological
onwards examination, onwards examination, q1y onwards cal examina- onwards examination,
q1y tion, q1y q1y
Leukemia/ From birth Blood testso, q – – – – – – From birth - Complete – –
lymphoma 3-4 m blood count
(prior leu-
kemogenic
drugs), q 1y
Prostate – – From 40y - PSA, q 1y – – – – – – – –
cancer onwards
General From birth to - Complete Beginning in - Comprehensive From birth to - Complete From birth to - Clinical From birth to - Whole physi- From birth to - Complete
assessment 18y physical infancy physical examina- 18y physical 17y examination 18y cal examina- 17y examination, q
examination, q tion, including examination, with specific tion, q 4-6 m 3-4 m
3-4 m neurologic exami- q 3-4 m attention - Cooperation
- Prompt assess- nation with high - Prompt to signs of with attending
ment by PCP index of suspicion assessment virilization physician
for any medical for rare cancers by PCP for or early
concern and second malig- any medical puberty and
nancies in concern measure-
cancer survivors ment of
every 6-12 m blood pres-
sure, q 6 m
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Table 4 (continued)
Surveillance Toronto Protocol (2016) [116] NCCN (2024) [115] AACR (2017) [117] GENTURIS (2020) [109] SEOM & AEGH (2020) [118] Japanese LFS Expert Group
Component (2021) [114]
From 18y - Complete Adulthood - Comprehensive From 18y - Complete From 18y - Clinical From 18y - Whole physi- From 18y - Complete
onwards physical physical exam onwards physical onwards examination onwards cal examina- onwards physical
examination, q including neuro- examination, with specific tion, q 6 m examination,
3-4 m logic examination q6m attention q6m
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received RT,
and family history of cancer (5-10y q 1y
before earliest diagnosis)
a
Blood tests include 17-OH-progesterone, total testosterone, dehydroepiandrosterone sulfate, and androstenedione
b
Blood tests include total testosterone, dehydroepiandrosterone sulfate, and androstenedione
c
Blood tests include total testosterone, dehydroepiandrosterone, androstenedione
d
First MRI with contrast, thereafter without contrast if previous MRI normal and no new abnormality
e
High-risk TP53 variants: Childhood cancer in individual/family members, variant that has already been associated with childhood cancers, and variants corresponding to a dominant-
negative missense variant
f
First MRI with contrast, thereafter contrast is not necessary as long as the previous MRI is normal and no new abnormalities are confirmed
g
Or five to ten years before the earliest breast cancer detection in the family (whichever comes first)
h
Or at the age of the earliest diagnosed breast cancer in the family, if < 20y
i
With and without contrast
j
Or mammogram, if MRI is unavailable (Breast MRI is preferred due to concerns regarding the risk of radiation exposure in P/LP variant carriers)
k
Breast MRI and abdominopelvic US to alternate with annual whole-body MRI (at least one scan q 6 m)
l
Or ten years before the earliest colon cancer detection in the family (whichever comes first)
m
Or five years before the earliest known colorectal or gastric cancer in the family
n
Whole-body MRI is performed from head to toe, including all limbs
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o
Blood tests include complete blood count, erythrocyte sedimentation rate, and lactate dehydrogenase
h Hour, m Month(s), MRI Magnetic resonance imaging, P/LP Pathogenic/likely pathogenic, PCP Primary care physician, PSA Prostate-specific antigen, q Every, RT Radiation therapy, US Ultra-
sound, y Year(s), LFS Li-Fraumeni syndrome, NCCN National Comprehensive Cancer Network, AACR American Association for Cancer Research, ERN-GENTURIS European Reference Network
on the Genetic Tumor Risk Syndromes, SEOM Sociedad Española de Oncología Médica, AEGH Asociación Española de Genética Humana
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among LFS patients with a history of previous malignancy [6, 123]. Given the significance of breast cancer in female
patients with LFS, a total bilateral prophylactic mastectomy has also been recommended; however, this decision
should be made according to each individual’s status of health and personal history of cancer, familial history, prin-
ciples, and wishes [124].
2.6 Treatment
There is no approved and definite treatment for LFS, and most LFS patients undergo the conventional treatment strate-
gies available for each cancer [114]. The management of LFS almost entirely depends on a combination of surveillance
protocols, risk reduction strategies, and therapeutic interventions tailored to the specific tumor types and clinical char-
acteristics of affected individuals. The standard treatment regimens for LFS-related cancers have traditionally involved
DNA-damaging systemic cytotoxic chemoradiation, which can lead to subsequent tumors [125]. Meanwhile, recent
studies have explored alternative therapeutic strategies that may offer more targeted and less genotoxic options for
LFS patients. Table 5 presents recent and ongoing clinical trials focusing on LFS patients. The most common proposed
therapeutic candidates are:
Immune checkpoint inhibitors, chiefly the programmed cell death protein-1 and its ligand (PD-1/PD-L1)- and cytotoxic
T-lymphocyte-associated protein-4 (CTLA-4)-targeting antibodies, have shown promising clinical activity in various solid
tumors and hematologic malignancies associated with LFS [126, 127]. By blocking inhibitory signaling pathways in the
tumor microenvironment, these agents could enhance the antitumor immune response, potentially leading to tumor
regression and prolonged patient survival [128]. Studies evaluating immune checkpoint inhibitors as monotherapy or
in combination with other therapeutic modalities are underway to assess their efficacy and safety in individuals with
LFS-associated cancers, including the United States Food and Drug Administration (FDA)-approved Nivolumab and
Pembrolizumab, and FDA-approval pending Sintilimab – which has been recently approved and included in the National
Reimbursement Drug List (NRDL) of China (Table 5) [129–135].
Adoptive cell therapy, including chimeric antigen receptor (CAR) T-cell therapy and tumor-infiltrating lymphocyte (TIL)
therapy, is another proposed approach for the treatment of LFS-associated malignancies [136, 137]. CAR T-cell therapy
involves engineering the patients’ T cells to express chimeric antigen receptors targeting specific tumor antigens, while
TIL therapy involves isolating and expanding tumor-infiltrating lymphocytes with antitumor activity ex vivo before rein-
fusion into patients [138]. The CAR T-cell-based combination strategies have demonstrated improved overall survival in
previous studies [139, 140].
2.6.3 Cytokine‑based therapies
Cytokine-based therapies, such as interleukin-2 (IL-2) and interferon-alpha (IFN-α), modulate the immune response and
enhance the antitumor activity of immune effector cells, including T cells and natural killer (NK) cells [141, 142]. Cytokine-
based therapies have been investigated as either monotherapy or in combination with other immunotherapeutic agents
for LFS-associated malignancies [143–145].
2.6.4 TP53 reactivators
Small molecule drugs designed to reactivate mutant TP53 proteins represent a promising therapeutic strategy for indi-
viduals with LFS-associated tumors [146, 147]. Eprenetapopt (PRIMA-1Met, APR-246) and RITA (Reactivating p53 and
Inducing Tumor Apoptosis) have shown preclinical efficacy in restoring the transcriptional activity, inducing cell cycle
arrest, and promoting apoptosis in cancer cells with dysfunctional TP53 [133, 148–150].
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Table 5 Recent and ongoing registered trials for documented Li-Fraumeni syndrome and TP53 mutation
Trial group Clinicaltrials.gov ID Study status Country Study type Study population Intervention(s) Measured primary outcomes
Monotherapy NCT01981525 Completed USA Phase I trial Adults (> 18) with docu- Metformin Tolerability of metformin, up to
mented positive germline 2 years (toxicity assessment by
TP53 mutation CTCAE v4.0), plus the effect of
metformin administration on cir-
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exercise
NCT05512377 Active, recruiting International multi- Phase II trial Adult (> 18) patients with Brigimadlin ORR in patients, up to 30 months
center locally advanced/metastatic, (BI 907828)
MDM2 amplified, TP53 wild-
type biliary tract/pancreatic
ductal adenocarcinoma, and
other solid tumors
Combination NCT06088030 Active, recruiting China Phase II trial Under-18 children and young Arsenic trioxide ORR four weeks after the combina-
therapy adults with pathological combined tion therapy
diagnosis basis of malignant with chemo-
tumor and germline or therapy
somatic P53 mutations*
NCT03377725 Withdrawn China Phase III trial Adult patients (> 18) with Arsenic trioxide RFS in patients, up to 6–8 months
MDS and Decit- after complete release
abine
NCT03381781 Unknown status China Phase II trial Adults (> 18) AML patients Arsenic triox- RFS in patients, up to 6–8 months
with p53 mutations ide, Decit- after complete release
abine, and
Cytarabine
NCT06088030 Active, recruiting China Phase II trial Child and young adult (< 18) Arsenic trioxide ORR four weeks after the combina-
p53-mutated patients with in combina- tion therapy
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Table 5 (continued)
Trial group Clinicaltrials.gov ID Study status Country Study type Study population Intervention(s) Measured primary outcomes
Review
NCT04277442 Active, not recruit- USA Phase I trial Adult (> 18) patients with Nivolumab in Incidence of adverse events and
ing newly diagnosed TP53- combination response rate, up to 3 cycles
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mutated AML with Decit-
abine and
Venetoclax
NCT05280626 Not started Undefined Phase II trial Adult (> 18) DLBCL patients Combination Complete response rate, up to one
with P53 mutation with of Sintilimab year
PD-L1 expression and R-CHOP
NCT04023916 Unknown status China Phase II trial Adult (> 18) TP53-mutant Combination Complete remission rate, every
and PD-L1-positive DLBCL of Sintilimab three months until thirty months
patients and R-CHOP after the last patient’s enrollment
NCT06366347 Not started USA Phase II trial Adults (> 18) patients with Letrozole/ Median PFS in patients, up to
advanced/recurrent ER + , Abemaciclib 2 years
MMRP, TP53 wild-type endo- vs Pembroli-
metrial cancer zumab
Discover Oncology
NCT04159155 Active, recruiting Canada Phase II/III trial Adult (> 18) patients with Radiation Three-year DFS in patients
pure serous endometrial therapy (EBR),
carcinoma or other histo- high-dose-
types (endometrioid and rate vaginal
clear cell) with abnormal/ brachy-
mutant-type p53 therapy, and
Niraparib
(2024) 15:561
NCT05197192 Active, recruiting Germany Phase III trial Adult (> 18) patients with Acalabrutinib, PFS 50 months after FPI
documented CLL/SLL Obinutu-
requiring treatment accord- zumab and
ing to at least one of the Venetoclax
following: 17p-deletion,
TP53-mutation, or complex
karyotype (3 or more chro-
mosomal aberrations in 2 or
more metaphases)
NCT02909972 Active, recruiting USA Phase I trial Adult (> 18) patients with Sulanemadlin Safety and tolerability of mono-/
relapsed/refractory AML or (ALRN-6924) combination therapy of
Advanced MDS with wild- as mono- Sulanemadlin with Cytarabine
type TP53 therapy or until 30 days after the last treat-
combination ment cycle
therapy with
Cytarabine
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Table 5 (continued)
Trial group Clinicaltrials.gov ID Study status Country Study type Study population Intervention(s) Measured primary outcomes
NCT03931291 Completed USA Phase II trial Adults (> 18) with TP53 Combination RFS in patients with TP53 mutated
mutated AML or MDS fol- therapy of AML or MDS after HSCT
lowing ASCT Eprenetapopt
(APR-246)
Discover Oncology
with Azaciti-
dine
NCT02448329 Completed South Korea Phase II trial Children and young adults Combination ORR in patients after eight weeks
(< 20) with advanced TP53- therapy of
mutation harboring gastric Adavosertib
adenocarcinoma, resistant (AZD1775)
to first-line 5-FU/platinum- with Pacli-
(2024) 15:561
NCT01464086 Completed France Phase III trial 5–71 year old patients with Whole body Incidence of cancer during the first
study P53 mutation MRI three years
*
with previously shown partial/complete response
AML Acute myeloid leukemia, BR Bendamustine and Rituximab, CLL Chronic lymphocytic leukemia, CTCAE Common Terminology Criteria for Adverse Events, DLBCL Diffuse large B-cell lym-
phoma, DFS Disease-free survival, DW-MRI Diffusion-weighted magnetic resonance imaging, EBR External Beam Radiation, ER Estrogen receptor, FCR Fludarabine, Cyclophosphamide, and
Rituximab, GVHD Graft-versus-host disease, HSCT Hematopoietic stem cell transplant, IGF-1 Insulin-like growth factor 1, IGFBP3 Insulin-like growth factor binding protein 3, MDM2 Mouse
double minute 2 homolog, MDS Myelodysplastic syndrome, MMRP Mismatch repair proficient, MRI Magnetic resonance imaging, ORR Objective response rate, OS Overall survival, PET Posi-
tron emission tomography, PFS Progression-free survival, R-CHOP Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone, RFS Relapse-free survival, STIR Short Tau inversion
recovery
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DNA damage response (DDR) pathway-targeting agents, such as poly(ADP-ribose) polymerase (PARP) inhibitors and
ataxia telangiectasia and Rad3-related (ATR) inhibitors, have shown efficacy in preclinical models of LFS-associated
malignancies, particularly in tumors with homologous recombination deficiency (HRD) [151–154].
Bruton’s tyrosine kinase (BTK) inhibitors are a class of targeted therapeutic agents that are generally considered in the
treatment of B-cell malignancies, including B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL)
[23, 155, 156]. BTKi is vital in B-cell receptor signaling, lymphocyte activation, and proliferation [157]. Small molecule
BTK inhibitors irreversibly bind to the active site of BTK, thereby inhibiting its kinase activity and downstream signaling
cascades, thus disrupting B-cell receptor signaling and promoting apoptosis of malignant B cells [158]. Ongoing research
efforts try to evaluate the safety and effectiveness of BTK inhibitors, such as Acalabrutinib, in combination with other
targeted therapies for LFS patients [156].
2.6.7 MDM2/X inhibitors
MDM2/X inhibitors disrupt the interaction between murine double minute 2 (MDM2) or its homolog murine double
minute X (MDMX) and the tumor suppressor protein p53. This interaction basically leads to apoptosis evade. By inhibiting
MDM2/X, these small molecule inhibitors restore p53 function, leading to cell cycle arrest, apoptosis, and tumor growth
inhibition [159]. From several experimental agents of this class, Milademetan (DS-3032b), Sulanemadlin (ALRN-6924),
and Brigimadlin (BI 907828) are extensively studied, showing promising results in the very early trials [146, 160–163].
2.6.8 Monoclonal antibodies
Monoclonal antibodies (mAbs) specifically target the antigens expressed on the surface of cancer cells or immune cells
in the tumor microenvironment. Initiating various mechanisms of action, including antibody-dependent cellular cyto-
toxicity (ADCC), complement-dependent cytotoxicity (CDC), and blockade of tumor growth signaling pathways, several
mAbs, such as Rituximab (anti-CD20), Obinutuzumab (anti-CD20), and Magrolimab (anti-CD47), are under investigation
for LFS patients [164–167].
2.6.9 Arsenic trioxide
Arsenic trioxide is a cytotoxic agent primarily used in treatment-resistant leukemia [168]. Preclinical studies have provided
strong evidence for the potential positive impact of arsenic on the survival of LFS patients [169]. Widely considered in
early-phase trials of LFS treatment nowadays, arsenic trioxide is generally well-tolerated, but it could result in serious
adverse effects, including QT interval prolongation, cardiac arrhythmias, hepatotoxicity, and neurotoxicity [170–172].
Close monitoring of cardiac function, electrolyte levels, and hepatic function is recommended during treatment with
arsenic trioxide to minimize the risk of adverse events.
2.6.10 Other agents
Some existing medications and agents have also been explored as adjuvant LFS treatments. Metformin, a widely used
oral antidiabetic agent, has attracted attention for its potential anticancer properties beyond its glucose-lowering effects
[173, 174]. Metformin acts primarily by activating AMP-activated protein kinase (AMPK), a master regulator of cellular
energy homeostasis, leading to inhibition of mTOR signaling, suppression of hepatic gluconeogenesis, and modulation
of cellular metabolism [175, 176]. Although Metformin might not be the primary choice of treatment in LFS patients,
given its efficacy in modulating the metabolic profile, the low cost, and accessibility, it could be considered as a pre-
ventive agent, especially in individuals with metabolic disorders or obesity-associated cancers [177, 178]. Likewise,
nicotinamide riboside, the precursor of nicotinamide adenine dinucleotide (NAD+), could lead to increased NAD+ levels,
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thereby activating sirtuins and other N AD+-dependent enzymes involved in DNA repair, chromatin remodeling, and
mitochondrial function [179–181]. Previous studies have suggested that nicotinamide riboside enhances cellular stress
resistance, inhibiting tumorigenesis and promoting cancer cell apoptosis [182, 183].
The chemopreventive approaches, using medications such as Tamoxifen and Raloxifene, have also been proven effec-
tive [184], but are still controversial due to their adverse effects and low patient compliance.
2.7 Challenges
LFS, and the broader context of TP53 mutation research, face various challenges affecting both patients and healthcare
providers, including:
Although TP53 is one of the most frequently mutated genes in cancer, developing therapies that effectively target mutant
TP53 has proven difficult.
Variants of uncertain significance (VUS), the mutations that their impact – whether pathogenic or benign – on the molecu-
lar function and cancer risk is not fully understood, impose clinical challenges in genetic counseling, risk assessment,
potential surveillance protocols, and decision-making for both patients and healthcare providers [185]. Guidelines lack
clear recommendations for this population, as the cancer risk associated with VUS is uncertain and lacks sufficient data.
Although in silico models deliver useful predictions, these models are generally not sufficient to guide clinical decision-
making [186]. Meanwhile, the Clinical Genome Resource (ClinGen) TP53 variant curation expert panel has introduced
a set of guidelines launched to classify TP53 variants, provide consistent and reliable interpretations of their clinical
significance, and help distinguish pathogenic mutations from benign variants and VUS [187, 188].
Differentiating between germline and somatic mutations is one of the major challenges with TP53 mutations identified
through NGS. While the inherited germline mutations lead to LFS, somatic mutations are not heritable. When a TP53
mutation is detected via an NGS panel, it is not immediately clear whether it is germline or somatic–possibly originat-
ing from clonal hematopoiesis of indeterminate potential (CHIP) [115]. Misinterpretation of somatic TP53 mutations as
germline can lead to unnecessary cancer surveillance in individuals who do not have LFS. Moreover, the detection of low
variant allele frequencies (VAF) in TP53 mutations adds complexity to the interpretation. VAF represents the proportion
of sequencing reads containing a variant, and low VAFs suggest somatic mutations arising from clonal hematopoiesis
rather than true germline mutations [189].
NGS panels often include TP53 to identify mutations for tumor profiling or assessing hereditary cancer risk. In older
adults, however, or those with CHIP, TP53 mutations detected in blood or bone marrow samples may be false positives
for germline testing, leading to misdiagnosis [190]. Consequently, patients with a CHIP-related TP53 mutation might be
unnecessarily subjected to LFS cancer surveillance for solid tumors due to the miscalculated cancer risk [115]. Moreover,
TP53 mutations with low VAF may lead to clinical dilemmas for testing family members, as the mutation may be somatic
rather than germline.
LFS overlaps with some other cancer-predisposing syndromes, complicating the diagnosis and risk assessment. CHEK2
(checkpoint kinase two) and BRCA1/2 (breast cancer genes 1 and 2) are among the most famous LFS-mimicking muta-
tions. For instance, mutations in CHEK2—also a tumor suppressor gene—referred to as the ‘CHEK2-associated Li–Frau-
meni syndrome’ or ‘Li-Fraumeni syndrome 2’, are occasionally misclassified as a subtype of LFS [191]. CHEK2 encodes a
serine/threonine kinase regulating the cellular response to DNA damage, and its mutations result in a tumor predisposi-
tion syndrome, associated with a moderately increased risk for later-onset development of less broad cancers, including
breast, prostate, and gastrointestinal tumors [191–193]. Moreover, CHEK2 is considered a low-penetrance gene compared
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to TP53, suggesting that not all individuals with CHEK2 mutations will develop cancer [194]. Studies have highlighted
the clear and significant distinctions in the clinical presentations of TP53 and CHEK2 pathogenic variant carriers and the
lack of association between CHEK2 and TP53-related LFS [195]. While both TP53 and CHEK2 are involved in DNA repair
and tumor suppression, CHEK2 mutations do not confer the same features as LFS, and since it could lead to inappropriate
management and suboptimal surveillance, their classification as an LFS subtype is generally discouraged.
As only a small proportion of LFS patients show long-term adherence to the surveillance protocols, the long-term follow-
up data on LFS patients, particularly in relation to the effectiveness of surveillance programs and therapeutic interven-
tions, is limited, negatively affecting the development of clinical evidence-based prevention and treatment guidelines
[196]. The impact of intensive screening on patient survival and quality of life over long periods is not fully understood
so far, and data on the long-term risks and complications, including the risks of radiation exposure from frequent imag-
ing, are rare.
Lifelong cancer surveillance is essential for patients with confirmed pathogenic TP53 mutations. However, striking the
right balance between early cancer detection and overdiagnosis still remains a significant challenge [197]. Extensive
screening protocols, often including annual whole-body MRIs, can lead to false-positive results or detection of indolent
cancers that may never progress to a clinically significant disease. Meanwhile, some patients may not follow the full
range of recommended screenings due to a lack of resources or understanding of the significance of TP53 mutations,
potentially leading to missed early detection opportunities.
2.7.7 Access to care
Access to genetic testing and specialized cancer care for individuals at risk of or diagnosed with LFS varies widely by
region and healthcare system [198]. In some areas, the availability of genetic testing, surveillance, and specialized treat-
ments may be limited, creating disparities in patient outcomes. The cost of genetic testing, preventive surgeries, or
frequent cancer screenings can be prohibitive for some families, potentially leaving patients with suboptimal care or
late-stage cancer diagnoses. Moreover, not all clinicians are fully aware of LFS or the need for comprehensive genetic
testing in patients with a family history of cancers, leading to inadequate care in some cases.
The management of LFS requires a multidisciplinary approach, involving geneticists, oncologists, surgeons, radiologists,
psychologists, and other specialists. Coordinating care across these domains can be difficult, particularly in healthcare
settings without established protocols for hereditary cancer syndromes.
2.7.9 Psychosocial burden
The psychosocial challenges faced by individuals with LFS are significant, as it often affects multiple generations within
a family, leading to fear of developing cancer and anxiety about passing the mutation on to offspring [199]. The ongoing
stress of living with an increased risk of cancer, along with the emotional toll of frequent surveillance, can be overwhelm-
ing for patients and their families.
3 Future directions
Advancements in genomic technologies have facilitated the identification of novel therapeutic agents and the devel-
opment of targeted therapies for LFS-associated malignancies. Novel cancer therapies, including various cancer immu-
notherapy modalities, checkpoint inhibitors, adoptive cell therapies, and various agents and methods of targeted
therapy, hold promise in improving treatment outcomes and reducing cancer burden in individuals with LFS (Table 5).
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Additionally, ongoing research efforts aim to elucidate the molecular mechanisms underlying LFS pathogenesis and
identify potential biomarkers for early detection and risk stratification. Longitudinal cohort studies and population-
based registries are essential in clarifying the natural history, risk factors of recurrence, and outcomes associated with
LFS. Furthermore, molecular epidemiological studies leveraging genomic technologies and bioinformatics analyses offer
insights into the genetic determinants, mutational signatures, and clonal evolution patterns underlying LFS-associated
tumorigenesis, guiding precision medicine approaches and targeted interventions tailored to the unique molecular
profiles of individual tumors.
4 Conclusions
Li-Fraumeni Syndrome poses significant challenges in clinical management due to its diverse spectrum of associated
malignancies and the need for lifelong surveillance and interventions. A comprehensive understanding of the molecular
basis, clinical manifestations, diagnostic criteria, screening strategies, and management options for LFS is crucial for opti-
mizing patient care and outcomes. Continued research efforts aimed at clarifying the underlying mechanisms, optimum
and effective surveillance strategies, and developing targeted therapeutic approaches are essential for improving the
prognosis of individuals affected.
Acknowledgements Parts of the figures were created using Servier Medical Art, licensed under CC BY 4.0 (https://creativecommons.org/licen
ses/by/4.0/).
Author contributions MSH: Conceptualization, Data Curation, Visualization, Writing—Original Draft and Review & Editing.
Funding None.
Data availability All data generated during this study are included in the published article.
Declarations
Ethics approval and consent to participate Not applicable.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which
permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to
the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You
do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party
material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If
material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds
the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativeco
mmons.org/licenses/by-nc-nd/4.0/.
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