Tumor Spectrum, Surveillance, and Emerging Prevention Strategies in Li-Fraumeni Syndrome

Introduction

Few hereditary cancer syndromes combine the rarity of Li-Fraumeni syndrome (LFS) with the depth to which it has been studied. Li and Fraumeni first described, in 1969, an unusual clustering of childhood rhabdomyosarcomas and early-onset cancers across the same families, and hypothesised an underlying dominant predisposition that had not yet been recognised.^1-2 Twenty-one years later, Malkin and colleagues provided the molecular explanation, identifying germline TP53 mutations in affected kindreds;³ subsequent studies refined the epidemiological picture⁴ and set the stage both for the genetic counselling and surveillance protocols now in routine use and for the first prospective chemoprevention trial in this disease. The clinical definition of the syndrome has continued to expand. That limit was pushed even further in 2021, when the LIFE Consortium reanalysed the IARC TP53 database and introduced the term ‘Li-Fraumeni spectrum’ for variant carriers who do not meet the classical testing criteria, a population that is now increasing rapidly since multi-gene panel testing is becoming part of routine oncology practice.⁵ The TP53 gene resides at 17p13.1 and codes for p53, a transcription factor that detects genotoxic stress as well as abnormal oncogenic signalling. Upon activation, it can stop the cell at either the G1/S or G2/M cell cycle checkpoints, induce nucleotide excision repair, push a cell towards senescence, or it can send that one on a path to apoptosis—different roads sharing a common destination: the removal of, or at least permanent seclusion of, cells containing genomic. Utilizing a “Li-Fraumeni-like” phenotype for identification helps fill the holes of classic criteria, particularly in low-middle income countries, where people cannot wait for multi-gene panel testing.^6-8 In LFS, one TP53 allele is already compromised from conception. When somatic mutation or deletion abolishes the remaining copy, p53 activity is lost entirely and the cell is free to accumulate further tumorigenic changes. The phrase ‘guardian of the genome’ has become a cliché, but it does capture why haploinsufficiency at this locus carries consequences across virtually every tissue.⁷

The cumulative lifetime cancer risk is close to 70% in men and higher than 90% in women, and even higher penetrance in women has been reported in some series when follow-up is prolonged.^9-10 This risk is not confined to a single cancer event: germline TP53 carriers are at an approximately 83-fold increased risk of developing multiple primary malignancies compared with the general population,^11-12 and published case series report individuals with five or more distinct primary cancers.¹³ The testing criteria have evolved dramatically from the initial 1988 definition,¹⁴ which included a proband with sarcoma at age <45, a first-degree relative with any cancer <45, and one more affected relative.In practice these criteria were too narrow and excluded many carriers, especially children harbouring de novo mutations. The Chompret criteria went some way to correcting this, first appearing in 2001 and revised in 2009 and again in 2015.^15-17 They added the following three tumour types, adrenocortical carcinoma, choroid plexus carcinoma and embryonal anaplastic rhabdomyosarcoma, as single indication for testing regardless of family history, and extended breast cancer prior to age 31, and the occurrence of two or more LFS-spectrum tumours prior to age 46. The 2020 ERN GENTURIS guidelines went one step further, highlighting that interpretation of variants is to be performed in the context of epidemiological, phenotypic, bioinformatic and functional data and should not solely be based on clinical criteria.¹⁸

Molecular Basis and Genetic Architecture

Approximately 80% of LFS-related germline TP53 mutations are missense variants located in the central domain involved in binding DNA. Six codons are mutated considerably more frequently than expected by chance: R175H, G245S, R248W, R248Q, R249S, and R273H, together harboring most of the recurrent pathogenic variants.¹⁹ Not all missense variants act the same. The majority are rather simple oncogenes, abolishing transcriptional activity, but there is a subset that in addition to losing transcriptional activity due acquiring gain-of-function (GOF) properties: the mutant protein interacts with co-regulators such as NF-Y and p63, promotes cell invasion, reprograms metabolism and desensitizes against cytotoxic drugs.²⁰ Whether an individual variant acts as a dominant-negative, with mutant p53 tetramers shutting down the remaining wild-type allele, or just as a loss-of-function allele seems to have impact on penetrance and age of onset, a distinction that is now incorporated into the GENTURIS risk stratification model.¹⁸

Beyond the genotype-phenotype relationships described above, formal risk-prediction tools increasingly translate variant class and family history into individualised estimates of malignancy risk. LFSPRO, a Mendelian statistical model incorporating pedigree and variant data, estimates the probability of carrying a deleterious TP53 variant and the risk of subsequent primary cancers, and has shown superior discrimination compared with the Chompret criteria in both retrospective and prospective genetic-counselling cohorts.²¹ In parallel, in silico splice-prediction algorithms such as SpliceAI are being incorporated into TP53 variant classification frameworks; work combining SpliceAI predictions with minigene functional assays and genotype-phenotype correlation across international registries has shown that a subset of exonic variants previously considered benign or of uncertain significance in fact disrupt splicing and is associated with earlier-onset, LFS-signature cancers, indicating that classification based on predicted amino-acid change alone can underestimate pathogenicity.²² Together, these tools support the clustering of TP53 variants, including recognised founder variants such as p.R337H, into risk strata that may in future inform the intensity and starting age of surveillance.

However, the TP53 mutation itself is not the only genetic factor influencing age of onset and penetrance. The MDM2 promoter polymorphism SNP309 (rs2279744) increases MDM2 expression and thus p53 degradation; female G allele carriers have been generally observed to develop cancer about 10 years earlier than those with the T allele.²³ Telomere length offers an additional layer: shorter leukocyte telomeres have been associated with earlier tumour onset in LFS populations, an observation likely reflective of the further chromosomal instability that critically shortened telomeres bring to a cell that has lost p53-based genome surveillance already.²⁴ Copy number variation rates are also elevated in LFS families, pointing to a genomic instability phenotype that extends beyond the TP53 variant itself.²⁵

TP53 noncoding variants and mosaic mutations are increasingly recognised contributors. Somatic mosaicism arising post-zygotically produces an intermediate phenotype in which cancer risk varies with the proportion of mutation-carrying cells and the tissues involved; its detection requires sensitive sequencing methods and has direct implications for cascade family testing.^26-27 De novo TP53 mutations, occurring in families with no prior cancer history, account for an estimated 7–20% of LFS cases and may paradoxically be identified at younger ages precisely because the absence of family history delays clinical suspicion.^26-27

A distinct geographical dimension deserves mention. In southern Brazil, the TP53 p.R337H founder variant is present in approximately 0.3% of the general population. This tetramerisation domain variant produces a protein that is partially functional under physiological conditions but destabilises at mildly elevated temperatures, resulting in an attenuated phenotype dominated by adrenocortical carcinoma in childhood and breast cancer in adult women.²⁸Analysis of the de Andrade et al. Lancet Oncology cohort of 524 TP53 carriers demonstrated that cancer incidence and tumour type distribution differ meaningfully by variant class, with DNA-binding domain hotspot mutations carrying higher penetrance than tetramerisation domain or splice-site variants.⁹

Clinical Tumour Spectrum

The range of malignancies associated with LFS is broader than that of any other single hereditary cancer syndrome. The five core tumour types, adrenocortical carcinoma, breast cancer, CNS tumours, osteosarcoma, and soft tissue sarcomas, account for the plurality of diagnoses, but the phenotype extends to a long tail of additional cancers occurring at significantly elevated rates in TP53 mutation carriers (Table 1).^15,9,29 The LFS-associated cancer landscape is further characterised by early age of onset and a high rate of metachronous second and subsequent primary tumours.^13,30

Pediatric presentations

Osteosarcoma is the most common paediatric tumour in LFS, accounting for roughly 30% of diagnoses in this age group. It tends to occur at the same anatomical sites as sporadic osteosarcoma and generally responds to standard neoadjuvant chemotherapy, although the underlying germline TP53 defect alters the risk-benefit balance of several treatment components. Alkylating agents and anthracyclines impose a heavy genotoxic burden on cells that already lack p53-dependent apoptosis, considerably increasing the risk of treatment-related secondary neoplasms.³¹ Platinum-based regimens carry an additional risk of cumulative ototoxicity requiring dedicated audiological monitoring,^32-33 and chemotherapy-induced oral mucositis represents a further significant source of morbidity in paediatric patients.³⁴ Radiation, occasionally used as an adjunct in osteosarcoma, poses particular dangers in TP53 carriers and is addressed specifically in the treatment section below.

Childhood adrenocortical carcinoma carries the strongest positive predictive value for underlying germline TP53 mutation of any single tumour type. With a background incidence of only 0.2–0.3 per million children per year, the diagnosis of ACC in a child, particularly under five years of age, effectively demands germline TP53 testing irrespective of family history, and ACC accounts for approximately 27% of all paediatric LFS-associated malignancies.^15,11 At the molecular level, paediatric ACC is characterised by copy-neutral loss of heterozygosity involving chromosomes 11 and 17 in association with germline TP53 variants, together with IGF2 overexpression and recurrent somatic mutations in ATRX and CTNNB1.³⁵ A geographic exception of note is southern Brazil, where the TP53 p.R337H founder variant elevates childhood ACC incidence 10–15-fold above the global average.^28,36-37

Central nervous system tumours account for approximately 25% of paediatric LFS malignancies and span a wide histological range. Choroid plexus carcinoma is nearly pathognomonic for the syndrome: germline TP53 mutations are found in approximately 50% of affected children, and any child with this diagnosis warrants immediate referral for genetic assessment.^38-39 Among older children and adults, H3-wildtype glioblastoma and diffuse intrinsic pontine glioma predominate; medulloblastomas and ependymomas are also recognised LFS-associated diagnoses.^39-40 A 2023 case series from Children’s National Hospital suggested that early surgical resection, informed by surveillance MRI, correlated with improved outcomes for CNS tumours in pediatric LFS patients.⁴¹ Soft tissue sarcomas — predominantly rhabdomyosarcoma, undifferentiated pleomorphic sarcoma, and leiomyosarcoma — form the bulk of the core paediatric tumour spectrum.⁴² There is a smaller but not insignificant proportion of blood cancers, which account for about 4% of LFS-related diagnoses; hypodiploid ALL is over-represented in that group, and therapy-related myeloid neoplasms can develop years after cytotoxic treatment for a prior solid tumour.⁴³

Adult presentations

Breast cancer dominates the adult LFS phenotype in women: cumulative lifetime risk is in the region of 79%, median age at onset is around 34 years (two to three decades earlier than in the general population), and bilateral presentation is frequent.¹¹ A 2023 systematic review of germline TP53-associated breast cancer confirmed a lifetime risk of 80–90%, and noted that a meaningful proportion of very early-onset breast cancers carry germline TP53 mutations, supporting diagnosis before age 31 as an independent trigger for genetic testing.⁴⁴ Tumour biology is heterogeneous in this setting, with HER2-positive, triple-negative, and hormone receptor-positive subtypes all represented.⁴⁵

Soft tissue sarcomas remain quantitatively important in adults, accounting for approximately 27% of adult LFS tumours, while CNS malignancies continue to occur throughout adulthood, high-grade gliomas being the predominant histology in older patients.⁴² Among the non-core diagnoses, colorectal cancer is the most clinically significant, representing approximately 2.8% of LFS-associated cancers in the NCI cohort; extended pedigree analyses further point to elevated risks of gastric and oesophageal cancer.^29,46 Young non-smoker lung cancer, melanoma, prostate cancer, and pancreatic carcinoma round out the adult spectrum at lower but clinically relevant absolute frequencies.²⁹

In adults, haematological malignancies are a unique diagnostic quandary, as they may develop either from de novo haematopoietic TP53 loss or as a late effect of previous cytotoxic therapy. A population-based 2024 registry study including 121 LFS families documented haematological malignancies in 29% of them; ALL was the most common diagnosis, followed by non-Hodgkin lymphoma and MDS and CLL.^43,47 Importantly, almost all of these patients were cytotoxic therapy naïve, suggesting that the predominant driving force is de novo haematopoietic transformation rather than treatment-related disease.

Multiple primary tumours: the defining challenge

The propensity to develop multiple independent primary cancers is arguably the most clinically challenging feature of LFS. Because the germline mutation is present in every cell, any tissue that subsequently loses the residual wild-type allele is oncogenically permissive, independent of what has happened elsewhere. Cohort data consistently show second primary cancer rates above 40% in LFS survivors followed for 10 or more years.^13,30 A practical implication too often overlooked is that completion of treatment for an index tumour should prompt immediate reinstatement of full surveillance, and survivorship care for LFS patients must be built around the realistic expectation of future malignancies rather than the assumption of cure.

Table 1: Tumour spectrum in Li-Fraumeni syndrome: approximate frequency, typical age of onset, and key clinical implications.

†In female TP53 mutation carriers. ‡In paediatric patients. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CNS, central nervous system; GI, gastrointestinal; HGG, high-grade glioma; RT, radiotherapy. Frequencies adapted from Bougeard et al. ¹⁵, Kratz et al. ¹¹, and de Andrade et al. ⁹.

Cancer Surveillance and Clinical Management

Evidence base for structured surveillance

The first proof that outcome-altering intensive surveillance for LFS was feasible was provided by Villani and collaborators, whose 2011 prospective observational study opened TP53 mutation carriers to a structured protocol (clinical examination, annual WBMRI, abdominal ultrasound and biochemical screening) and showed a three-year overall survival of 100% versus 21% in a matched non-surveillance cohort.⁴⁸ Cancers detected by the protocol tended to be small and asymptomatic, and early-stage; those who were not screened generally presented with late-stage disease. Prolonged follow-up at 11 years yielded five-year overall survival in the surveilled group of 88.8% compared to 59.6% in controls, with a 2023 update incorporating new evidence and further sophisticating the protocol.^49-50

More recent data have both validated and refined this framework. A 2024 systematic review and meta-analysis across eight studies and 506 TP53 carriers confirmed an overall cancer detection rate of approximately 6% at baseline WBMRI, with 41 of 46 cancers identified at an early stage.⁵¹ The UK SIGNIFIED prospective programme reported 70% of detected tumours at an early stage, a 7.4% baseline cancer detection rate, and a 12% rate at the 12-month follow-up scan.⁵² A large single-centre series of 325 WBMRI scans in 75 adults demonstrated specificity of 95.5% and negative predictive value of 97.4% as a stand-alone tool, though benign incidental findings requiring additional investigation arose in 27.4% of scans.⁵³ These findings underpinned the 2017 international consensus guidelines endorsed by the NCCN, AACR, and the UK Cancer Genetics Group,^54,11-12 the content of which is summarised in Table 2.

Adherence to surveillance remains a significant clinical challenge. A 2023 study found poor mental health-related quality of life in 59.4% of LFS patients under surveillance, with high levels of fear of progression and psychological distress affecting the majority.⁵⁵ In a separately published adherence analysis, non-adherence was associated with younger age, lower income, and the absence of a recent cancer diagnosis.¹⁰ Psychosocial support is therefore an integral component of a functional surveillance programme, not a supplementary add-on.^56-57

A further frontier concerns extending early identification of TP53 carriers to the newborn period. Population-based neonatal screening for the TP53 p.R337H founder variant in southern Brazil has been running for over a decade and has brought forward the diagnosis of adrenocortical tumours to an earlier, more curable stage among screened carriers compared with unscreened relatives.⁵⁸ Decision-analytic modelling of population-wide TP53 newborn screening in the United States estimated a modest reduction in cancer-related mortality at an incremental cost-effectiveness ratio in the region of $106,000 per life-year gained, and concluded that further prospective data are needed before universal implementation could be recommended.⁵⁹ Newborn screening therefore remains a promising but still investigational extension of the surveillance paradigm rather than an established standard of care.

Table 2: Summary of consensus surveillance guidelines for Li-Fraumeni syndrome (adapted from Kratz et al. ¹¹ and Villani et al. ⁴⁷).

*Alternating with WBMRI every 6 months. CBC, complete blood count; DHEAS, dehydroepiandrosterone-sulphate; LDH, lactate dehydrogenase; WBMRI, whole-body MRI.

Treatment modifications in LFS patients

When a cancer arises in an LFS carrier, treatment broadly follows standard oncological protocols, but several critical adaptations are required. The most important concerns ionising radiation. Normally, p53 commits cells with radiation-induced DNA double strand breaks towards apoptosis; in the absence of that guard, damaged cells survive and mutate further, greatly increasing the risk of secondary malignancy inside formerly irradiated volumes. A retro­spective review in 2025 of 47 children with solid tumours associated with LFS demonstrated that radiotherapy recipients had a shorter median time to a second primary (13.3 years) and did worse once that second cancer developed.⁶⁰ Registry data confirm a higher subsequent malignancy rate in LFS patients treated with irradiation, and a recent Lancet Oncology re-view formally proposed the exclusion or modification of radiotherapy in all tumour types in this syndrome, at least for treatment protocols.^61-62 In breast cancer the consequences are the most drastic: bilateral mastectomy is recommended over breast-conserving surgery, which contralaterally removes the at-risk breast and negates the requirement for chest-wall irradiation.^63-64 For CNS tumours, maximal safe resection is the goal of surgeons in precisely avoiding or delaying radiotherapy; if irradiation is not deferrable, proton beam or other highly conformal technique is the modality with choice.⁴¹ In paediatric CNS tumours, neurotrophic factor expression in low-grade gliomas and ependymoma are prognostic,⁶⁵ and visual evoked potentials continue to be the principle non-invasive technique for monitoring optic pathway tumour function.⁶⁶ In sarcomas the successful combination appears to be chemotherapy plus limb-salvage surgery, with adjuvant radiotherapy excluded from the field as much as tumor anatomy permits.⁵⁸ Sarcopenia and nutritional depletion have recently been identified as clinically relevant prognostic indicators in children with sarcomas of the bone and soft tissue, and their systematic evaluation and management should be part of treatment planning.⁶⁷

Immunotherapeutic and molecularly targeted strategies are currently under investigation for LFS-associated tumours. GOF TP53 mutations suppress anti-tumour immunity, partly through PD-L1 upregulation and interference with interferon signalling in the tumour microenvironment;⁶⁸ eprenetapopt (APR-246), a small molecule that shifts missense mutant p53 towards a wild-type conformation, appears to reverse this immune evasion and restore T-cell-mediated tumour killing in preclinical models,⁶⁸ and the APR-246 plus azacitidine combination showed activity in a phase II study of somatic TP53-mutant haematological malignancies,⁶⁹ although whether these findings translate to germline-driven LFS cancers remains unclear. Cytotoxic and targeted regimens used for LFS-associated tumours, including temozolomide for recurrent high-grade glioma,^70-71 BRAF/MEK inhibitors for pathway-targetable tumours,⁷² and topoisomerase inhibitors in paediatric brain tumours,⁷³ broadly follow standard paediatric oncology protocols, but require the same TP53-informed caution regarding cumulative genotoxic exposure discussed above, together with attention to drug-specific safety considerations such as carboplatin hypersensitivity,⁷⁴ antiepileptic-cytotoxic drug interactions in CNS disease,⁷⁵ and supportive-care needs including pain management.^76-81 General lifestyle measures, avoidance of tobacco and alcohol, consistent sun protection, and substitution of CT with MRI or ultrasound whenever clinically feasible, are recommended for all LFS carriers to limit cumulative genotoxic and radiation exposure.

Emerging Research and Future Directions

Liquid biopsy and circulating tumour DNA

Imaging-based surveillance faces inherent limitations in resolution, anatomical coverage, and the interval between molecular transformation and macroscopic detectability. Cell-free DNA and ctDNA assays have emerged as potentially transformative complements to WBMRI in LFS. Wong and colleagues demonstrated that a multi-modal liquid biopsy platform detected cancer-associated signals in the peripheral blood of TP53 mutation carriers before tumours were visible on imaging, with a high negative predictive value.⁸² These results raised the prospect of blood-based surveillance as a between-scan monitoring tool, with sensitivity complementing MRI for tumours that fall below imaging resolution thresholds.

Technical validation in prospective LFS cohorts is underway, with particular focus on sensitivity at early tumour stages, specificity in the presence of clonal haematopoiesis, a common source of false-positive TP53-mutant fragments in older individuals, and clinical actionability of equivocal signals. The MILI trial incorporates ctDNA and other biomarker substudies that should provide important data on liquid biopsy performance in the context of structured WBMRI surveillance.⁸³ A dedicated multi-institutional effort, the CHARM (cfDNA in Hereditary And high-Risk Malignancies) consortium, has moved from retrospective feasibility work in LFS cohorts to the CHARM2 prospective randomised controlled trial, which is enrolling participants across several hereditary cancer syndromes, including LFS, to formally test whether cfDNA-based screening improves early cancer detection compared with conventional surveillance.⁸⁴ If validated, periodic ctDNA monitoring could allow rational personalisation of surveillance intensity, more frequent imaging when blood-based signals are positive, and potentially safer extension of intervals when they are persistently negative.

Chemoprevention: the MILI trial

The possibility of preventing cancer formation in LFS has moved from aspiration to clinical trial with the MILI (Metformin in Li-Fraumeni Syndrome) study, a phase II, open-label, randomised controlled trial in which 224 adults aged 16 or over with confirmed germline TP53 pathogenic variants are randomised 1:1 to oral metformin (titrated to 2 g daily) plus annual WBMRI, or surveillance alone, over five years.⁸³ The primary endpoint is a 50% reduction in new cancer events. Metformin was selected on the basis of preclinical evidence demonstrating that LFS patients and TP53-mutant mouse models exhibit elevated mitochondrial oxidative phosphorylation, and that metformin’s inhibition of complex I of the mitochondrial electron transport chain delays tumour onset in Trp53-mutant mice. Paediatric cohort expansion is under active consideration.^85-86 Results from the MILI trial are expected in the late 2020s.

The broader chemoprevention landscape in LFS is at an earlier stage. Aspirin’s anti-inflammatory properties have theoretical relevance for colorectal cancer risk, and observational data from Lynch syndrome suggest benefit in hereditary colorectal cancer, but no LFS-specific trial has been completed. PARP inhibitors and ATR/CHK1 inhibitors that exploit synthetic lethality with TP53 deficiency are being discussed in the research community but lack clinical trial evidence in LFS.²⁰ The MILI trial’s methodology sets a template that future chemoprevention efforts should match.

Precision risk stratification and future therapies

As LFS cohorts accumulate longitudinal data, variant-specific risk stratification is becoming realistic. The de Andrade et al. Lancet Oncology cohort showed that cancer incidence and tumour type differ substantially by variant class,⁹  and the LIFE Consortium went a step further by formally separating attenuated from classic LFS using variant properties alongside clinical criteria.⁵ Looking ahead, carriers of dominant-negative hotspot mutations, the highest-penetrance group, could reasonably receive intensified surveillance from birth and take priority in chemoprevention trials, whereas those with attenuated variants might be managed with lighter-touch monitoring schedules. Personalised risk tools incorporating variant type, MDM2 SNP309 status, telomere length, and family history are being developed in research settings.^19,9 A systematic WBMRI meta-analysis⁸⁷ and prospective single-centre data are providing the imaging performance data needed to calibrate these tools. ^53,88

The longer-term therapeutic frontier centres on restoration of p53 function. Small molecules that reactivate mutant p53, such as eprenetapopt and, more recently, the TP53 Y220C-selective reactivator rezatapopt (PC14586), now being assessed in the registrational phase II PYNNACLE trial, which has reported objective responses across several Y220C-mutant solid tumour types,⁸⁹ are conceptually compelling as prophylactic agents in LFS carriers of the relevant hotspot variants; however, existing efficacy data derive from treatment of established, mutation-matched tumours rather than germline carriers, and sustained whole-body use over decades raises formidable, still-unresolved questions of pharmacology, off-target toxicity, and long-term tolerance.^{6,68-69,90-95} Antigen-directed immunoprevention, including lipid-nanoparticle-formulated mRNA vaccines targeting tumour-associated or neoantigens, is being explored as a further preventive strategy in oncology more broadly;⁹⁶ in LFS specifically this remains a purely investigational concept, with no dedicated vaccine trial yet reported in TP53 carriers. Germline correction via gene editing remains strictly preclinical and carries ethical implications requiring broad deliberation before any path to clinical application can be charted. A more immediately approachable research direction is the characterisation of additional cancer predisposition genes in LFS-like families who lack identifiable TP53 mutations, as well as further delineation of the broader phenotypic spectrum in families with TP53 mutations not meeting classic clinical criteria;^97-105 candidate genes in the DNA damage response and telomere maintenance pathways would both extend the reach of genetic surveillance and open new windows for therapeutic targeting.^106-110

Conclusion

Fifty-five years after Li and Fraumeni described the first affected families, the syndrome that bears their names remains one of oncology’s most demanding clinical problems. Its central difficulty is not diagnostic, identifying a TP53 germline mutation is now straightforward, but biological and practical: how do you protect someone whose every cell carries the seeds of potential malignancy, across decades of life, through multiple sequential tumours? The progress made over the past 15 years has been real and consequential. Structured WBMRI-based surveillance has converted a diagnosis that once implied near-inevitable early mortality into a condition compatible with extended survival, and the evidence base justifying this approach is now sufficiently robust that failure to offer surveillance to a known TP53 carrier is difficult to defend clinically.

Several caveats temper this progress. Reported differences in tumour risk and spectrum across cohorts may reflect variant class and dominant-negative potential, ascertainment bias inherent to clinic-based registries — a bias that dedicated competing-risk statistical models have begun to formally correct for ¹¹¹ — heterogeneity in surveillance intensity and access, prior treatment exposure, and population-specific founder variants such as p.R337H, rather than true biological differences in penetrance,^21-22 disentangling these contributions will require larger, prospectively followed, population-ascertained cohorts. It is equally important to keep established and investigational interventions clearly distinct: whole-body MRI surveillance now rests on a reasonably mature evidence base, whereas metformin chemoprevention, ctDNA-based liquid biopsy, TP53-reactivating small molecules, and antigen-based immunoprevention remain, at this stage, promising research strategies rather than validated clinical tools, and should be presented and adopted accordingly.

Liquid biopsy platforms remain under active clinical investigation and may eventually offer a blood-based complement to imaging that catches what scans miss, pending confirmation in the prospective randomised trials now underway.

Acknowledgment

The authors thank “Fondazione per l’Oncologia Pediatrica ONLUS” for their dedicated patient care and scientific support.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The authors do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration

This research does not involve any clinical trials.

Permission to reproduce material from other sources

Not Applicable 

Author Contributions

• Antonio Ruggiero: Conceptualization, Methodology, Writing – Original Draft.
• Giorgio Attinà: Data Collection, Analysis, Writing – Review & Editing.

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