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A systematic review of high-grade glioma associated with Li-Fraumeni syndrome
Trent Kite1 . Vineetha Yadlapalli1,2 . Rhea Verma2 . Mokshal Porwal1 . John Herbst3 . Stephen Karlovits4. Rodney E. Wegner4 . Matthew J. Shepard1
Received: 17 October 2024 / Revised: 30 January 2025 / Accepted: 27 February 2025 / Published online: 10 March 2025 @ The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2025
Abstract
Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome characterized by an increased risk of early-onset and multiple tumors across various organ systems, predominantly linked to germline TP53 mutations. While commonly asso- ciated neoplasms include sarcomas, breast cancer, and adrenocortical carcinoma, the occurrence of high-grade gliomas (HGG), including glioblastoma multiforme (GBM), in LFS patients is less documented and typically presents at a younger age relative to sporadic cases. A systematic review following PRISMA guidelines was conducted, focusing on clinical studies and case reports that explore the association between HGG and LFS. A comprehensive PubMed search was used to capture relevant studies. The inclusion criteria focused on patients with a confirmed diagnosis of LFS and histopatho- logically verified HGG. A total of 248 articles were initially identified, with 8 studies meeting the final inclusion criteria after independent review and consensus. Overall, 8 studied reported on patients with either WHO grade 3 or 4 gliomas in the setting of LFS. In total these studies represent 12 patients, with 8 (66%) WHO grade 4, and 4 (33%) WHO grade 3. 9 (75%) patients underwent maximal safe resection, 5 (42%) underwent concurrent TMZ and EBRT. 9 (75%) patients underwent external beam radiation therapy (EBRT), 1 (8%) underwent intensity modulated radiation therapy (IMRT), and 1 (8%) underwent adjuvant treatment with tumor treating fields (TTF) therapy. Overall chemotherapy utilization was 75% with 9 patients receiving some form of chemotherapy. The median time to recurrence following initial treatment was 7 months (IQR: 2.00-7.00). Time to progression was variable, ranging from 5.1 months to 7 years. 64% of patients succumbed to their disease with a median OS of 17 months across studies. LFS associated HGGs are a genetically het- erogenous entity. Detailed study of outcomes reported in the literature with respect to these genetics will develop further insight into therapeutic response and prognostication.
Keywords Li-Fraumeni syndrome · Germline TP53 variant · High-grade-glioma · Precision-medicine
☒ Trent Kite Trenton.Kite@ahn.org
1 Department of Neurosurgery, Allegheny Health Network Neuroscience Institute, Pittsburgh, PA, US
2 Drexel University School of Medicine, Philidelphia, PA, US
3 Division of Neuro-Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA, US
4 Division of Radiation-Oncology, Allegheny Health Network Cancer Institute, Pittsburgh, PA, US
Introduction
Li-Fraumeni syndrome (LFS) is a rare familial cancer syn- drome [1]. The natural history of these patients is character- ized by a propensity to develop early and multiple tumors across multiple organ systems [2]. The most frequent genetic association is a germline TP53 mutation on chromosome 17 at the p13.1 locus, inherited in an autosomal dominant pat- tern [1-3]. Despite this, a great deal of genetic heterogeneity exists with respect to the specific variation at this locus [1, 4]. TP53 functions as a tumor suppressor gene involved in cell cycle coordination through nuclear transcription regu- lation [1]. Loss of function mutations predispose the cell to dysregulated proliferation and a propensity for tumor for- mation [1].
Classically associated neoplasms are sarcomas, breast cancer, adrenocortical carcinoma, leukemia, and various central nervous system (CNS) neoplasms [1]. The classi- cal criteria for LFS considered any patient younger than 45 years of age with sarcoma and a first/second degree relative with any cancer or sarcoma to be consistent with LFS [2]. The 2009 revised Chompret criteria expanded the defini- tion to include patients≤46 with any LFS related tumor and a first degree relative≤56 with any LFS related tumor or multiple primary tumors [2, 5]. The expansion of the clini- cal definition of LFS uncovers an entire subset of patients previously defined as sporadic tumors which may have been misclassified.
Glioblastoma multiforme (GBM), is a frequently occur- ring high-grade glioma (HGG) with a median survival of 14-16 months after multimodal therapy with surgical exci- sion, chemotherapy, and radiation [1]. In contrast to spo- radic forms, familial GBM and other HGG are extremely rare [6]. GBM patients typically present in advanced age with an incidence most common from 45 to 70 years of age [2]. Patients with LFS can present with GBM much younger, with reports as low as 22 years of age [1]. Recent estimates have reported the average age of primary brain tumor onset in LFS around 16 years of age [1]. Outcomes are often worse in tumors associated with LFS [1]. Addi- tionally, responses to certain chemotherapies like Temo- zolomide (TMZ) are ambiguous in the literature reporting on patients with LFS and germline TP53 mutation versus a patient with wild-type (WT)-TP53 status [1].
Data reported in the literature demonstrates that primary brain tumors are responsible for 16.4% of LFS cases, yet lacks detailed clinical characterization in presentation, his- topathology, and response to treatment [7]. The pathway of tumorigenesis in tumor predisposition syndromes is pro- posed to differ from non-syndromic CNS tumor patients [7]. Furthermore, ideal screening protocols for surveillance of LFS patients with CNS neoplasms lack widespread accep- tance [8]. Finally, with respect to the distribution of central nervous system (CNS) neoplasms choroid plexus tumors and low-grade gliomas are most associated with the LFS [1]. There exist gaps in the literature reporting on much rarer CNS neoplasm in LFS like High grade gliomas (HGG). Therefore, we sought to evaluate current understanding in the literature and summarize the data published on clinical outcomes.
Methods
Search strategy and eligibility criteria
We conducted a systematic search in accordance with the preferred reporting items for systematic reviews and meta- analyses (PRISMA) guidelines [8]. We attempted to broadly identify literature reporting on the association of HGG in the context of LFS. An emphasis was placed on identifying previous case series to inform relevant discussion points. The following phrase and search terms utilizing both MeSH and non-MeSH items was searched in PubMed: (Li-Frau- meni syndrome OR LFS OR Familial TP53 mutation OR germline TP53 mutation) AND (Glioma OR Glioblastoma multiforme OR Glioblastoma OR WHO grade 3 glioma OR WHO grade 4 glioma OR gliosarcoma OR anaplastic astro- cytoma OR high-grade glioma). No restrictions were placed on publication dates. The formal review protocol was as follows: two authors independently conducted the search based on pre-defined inclusion and exclusion criteria. Any disparity in the articles to be included in the final analy- sis was reconciled by group discussion. Additional, but relevant articles not captured in the search were identified manually via the snowball method. Case series, retrospec- tive and prospective cohort studies, case control, literature reviews, and randomized control trials were all deemed as appropriate study designs for inclusion into our analysis. Patients in these studies must have met the following crite- ria: clinical and genetic diagnosis of Li-Fraumeni Syndrome as well as at least one histopathologically confirmed diagno- sis of a WHO grade 3 or higher glioma. Non-English texts, preprint, and non-peer reviewed literature were excluded from analysis.
Statistical analysis
Descriptive statistics were performed in GraphPad Prism (V.10).
Quality assessment
A Joanna Briggs Institute checklist for observational stud- ies was applied to the articles intended for final analysis. Articles scoring≥6 were deemed appropriate quality for inclusion.
Results
Selection process
Our initial search process returned 248 full length texts. Initial review was based on title, abstract and screening for topic relevance to filter articles for selection. 135 texts were excluded at the title screening initial stage. The remain- ing 113 texts abstracts were reviewed by two independent authors and assessed on relevance and adherence to exclu- sion/inclusion criteria. Sixty-nine texts were excluded after this stage with a remining 44 texts eligible for full text review A group consensus was reached, and 7 articles were agreed upon for inclusion in final analysis. One additional article was manually identified from references during full text review. All 8 (100%) of these articles met the pre-spec- ified JBI quality threshold. AA summary of the previous reports of LFS associated HGGs are outlined in (Table 1). The selection process is summarized in the PRISMA flow- chart in (Fig. 1).
Figure 1. 2020 PRISMA flowchart. 248 articles were identified. 7 articles meeting inclusion and exclusion
criteria. 1 article was identified via snowball method and included in the final analysis totaling 8 articles.
Literature review summary
Table 1. Summary of high-grade glioma (WHO 3 or 4) cases including patients diagnosed clinically or genetically with LFS reporting treatment, pathologic, and clinical outcomes.
Overall, we identified 8 studies reporting on patients with either WHO grade 3 or 4 gliomas in the setting of LFS (Table 1). In total these studies represent 12 patients, with 8 (66%) WHO grade 4, and 4 (33%) WHO grade 3 gliomas. The following pathologies were reported: Gliosar- coma 1 (8%), Glioblastoma 6 (50%), Anaplastic Astrocy- toma 2 (17%), grade 3 undefined 2 (17%), diffuse midline glioma 1(8%). With respect to treatment 9 (75%) underwent maximal safe resection, however only 5 (42%) underwent concurrent TMZ and EBRT followed by additional cycles of TMZ (Stupp protocol) following resection. It should be noted that 2 (16%) patients reported by Nagane et al. were treated prior to the institution of this regimen as standard of care in HGG patients. 9 (75%) patients underwent external beam radiation therapy (EBRT), 1 (8%) underwent intensity
| Study | Patients(N) | WHO tumor grade | Primary management | Outcome |
|---|---|---|---|---|
| Xiaoyu et al. [1] | 1 | IV (GBM)1 | Resection+EBRT2+TMZ3+cyto- kine induced killer cell immunotherapy | Recurrence at 7 years (alive) |
| Fang et al. | 2 | 1: | 1: | 1: |
| [2] | III (HGG)5 | Resection+Chemo4 | Stable disease at time of report (alive) | |
| 2: | 2: | 2: | ||
| IV (GBM) | Resection+EBRT+TMZ | Spinal cord metastasis at 4 months (alive) | ||
| Guidi et al. | 1 | 1: | - | - |
| [3] | I V Gliosarcoma | |||
| Kibe et al. | 3 | 1: | 1: | 1: |
| [7] | III (HGG)5 | Biopsy+EBRT+TMZ+Avastin6 | Recurrence at1 7.0 months (death at 21.7 | |
| 2: | 2: | months) | ||
| IV (GBM) | Resection+EBRT+TMZ | 2: | ||
| 3: | 3: | Recurrence at 5.1 months (death at 18.6 months) | ||
| IV (GBM) | Resection+EBRT+TMZ+TTF7 | 3: | ||
| Recurrence at 9.2 months (death at 15.3 months) | ||||
| Garcia-Carde- nas [24] | 1 | III (Anaplastic Astrocytoma) | Resection+IMRT8+TMZ | Progression at 14 months (death at 17 months) |
| Messina et al. [11] | 1 | IV Diffuse midline glioma | Biopsy+EBRT | Recurrence following radiotherapy at 2 months (death at 4 months) |
| Nordfors et al. [15] | 1 | III (Anaplastic Astrocytoma) | Resection+EBRT | Stable after 6 years (alive) |
| Nagane et al. | 2 | 1: | 1: | 1: |
| [23] | IV (GBM) | Resection+EBRT+intrathecal | Recurrence at 7 months (death at 5 months) | |
| 2: | interferon beta | 2: | ||
| IV (GBM) | 2: | Recurrence immediately following primary | ||
| Resection+EBRT+EBRT boost+ACNU9 | treatment (death at 18 months) |
1Glioblastoma Multiforme, 2External beam radiation therapy 3Temozolomide, 4Carboplatin/Etoposide alternating with Cyclophosphamide/ Vincristine, 5Pathology was consistent with high grade glioma at least grade 3, 6 Bevacizumab, 7Tumor treating fields,8Intensity-modulated radiotherapy, 9Nimustine
Identification of studies via databases and registers
Identification
Records removed before screening:
Records identified from: Databases (n =248 )
Duplicate records removed (n =0 )
Records removed for other reasons (n =0)
Title screened (n =248 )
Reports excluded (n =135 )
Screening
Abstract screened (n =113 )
Reports excluded (n = 69)
Full text review (n = 44)
Reports excluded: Not meeting inclusion criteria (n = 35)
Non-English (n = 2)
Included
Studies included in review (n =7)
Manual search (n =1)
modulated radiation therapy (IMRT), and 1 (8%) underwent adjuvant treatment with tumor treating fields (TTF) therapy. Overall chemotherapy utilization was 75% with 9 patients receiving some form of chemotherapy, most commonly TMZ 6 (50%). Out of 7 cases reporting recurrence, the median time to recurrence following initial treatment was 7 months (IQR:2.00-7.00). Time to progression was variable, ranging from 5.1 months to 7 years. There was also 1 (8%) case with noted metastasis to the spinal cord, occurring at 4 months following initial treatment. Information regarding death status was reported in 11 patients with a frequency of 64%. Survival time was reported in 7 of the 11 cases report- ing on death with a median OS across studies of 17 months (range 10.15-18.6 months).
Discussion
Genetics
Germline mutations in the TP53 gene constitute 50-70% of LFS cases and is the pathognomonic gene alteration associ- ated with the syndrome [9]. Mutations in this gene affect transcriptional regulation of the cell cycle with subsequent dysregulation and a propensity for increased cellular pro- liferation [10]. The mutational profile of TP53 in LFS is extremely heterogenous, with over 1800 distinct mutations identified [2]. 70% of the mutations are missense, resulting in altered protein production, while 20% are nonsense or splice site variants with a subsequent absence of any protein
activity [1]. The exact breadth of the mutational landscape is undefined currently. There are a handful of recurrent mutations accounting for approximately 20% of reported mutations: P.R175H, P.G245S, P.R248Q, P.248 W, P.282 W, P.R273H [2]. There also exists variability in the penetrance of each specific variation, which is proposed to be influenced by location of the neoplasm, gender, and age [1]. Addition- ally, Wu et al. demonstrated that penetrance can be a func- tion of specific variation with the highest penetrance at 30 years of age seen with P.R248W (58%), and lowest with P.R213Q (21%) [1]. Interestingly, whole exome sequencing (WES) has demonstrated that genetics frequently seen in sporadic gliomas are often lacking in LFS gliomas [7, 11]. A typical mutational profile in a HGG would reflect PTEN, TERT promoter mutation, epithelial growth factor mutation (EGFR) amplification, and gain of chromosome 7 and loss of chromosome 10 [4, 7, 12, 13].
Additional work has been done to define genetic differ- ences stratified by age of onset [1]. The adult and young adolescent (AYA) cohort (0-15 years old) demonstrates a germline mutational frequency of TP53 in 3.75% of GBM cases, making this relationship extremely rare [1]. Further- more, certain mutational signatures such as the R.P282W amino acid substitution portend a better prognosis versus C. 584T>C variation which tends to predict a poorer prognosis in this group [1].
An additional role for IDH in LFS was proposed by Nordsford et al., who identified a case of LFS associated anaplastic astrocytoma with germline TP53 mutation and a single nucleotide variation in the ATRX gene [14]. Along the course of this patients life they developed a somatic IDH (R132H) somatic mutation and subsequently developed a HGG, suggesting a mediating role for somatic IDH muta- tions and the development of tumors in the background of distinct germline mutational profiles [14]. Sloan et al. simi- larly reported a relationship between germline TP53 vari- ant LFS patients with somatic IDH and ATRX mutants [15]. Another genetic event proposed to mediate the development of HGG in LFS patients is the deficiency of SMARCB1 [16]. Deficiency of this protein and a concomitant germline TP53 mutation has demonstrated increased propensity for HGG in patients with LFS [16]. Loss of SMARCB1 expres- sion may represent a seminal event in the pathogenesis of HGG in LFS and may be an opportunity for early screening if identified in LFS patients [16].
A relatively recent finding is that of NTRK2 gene fusion transcripts in patients with LFS [10]. NTRK1 gene fusions transcripts have been defined in LFS associated with dys- regulated cell growth and tumor development [10]. There is ongoing evaluation of the efficacy of the experimental drug Larotrectinib in LFS patients with this genetic signature [10]. In their article Messina et al. defined a rare population
of HGG patients with LFS who harbored a NTRK2 gene fusion transcript [10]. Relatively little is known, however targeted therapy like Larotrectinib may have utility in these patients [10].
Clinical manifestations
Tumors associated with LFS are thought to be separated in two distinct temporal patterns, childhood (0-15yrs, 22% of cases) and adult (16-50 years, 51% of cases) [1]. Childhood cases most frequently reveal low grade gliomas (LGG), medulloblastoma, and choroid plexus carcinoma [10]. Conversely, and while still rare adults are more likely to develop HGG [10]. Additionally, while sporadic (TP53 wildtype (WT)) gliomas can progress to higher grade forms, germline TP53 mutant gliomas have demonstrated a higher rate of progression compared to WT forms [10]. Given the increased likelihood of accelerated growth and incidence of malignancy in this population, widespread screening efforts have been developed for earlier identification [17]. How- ever, many centers lack the capability to identify proposed genetic prognostic factors in LFS patients due to an absence of established high throughput gene sequencing protocols and advanced DNA methylation profiling techniques [16]. Currently, it is a barrier to obtain uniformly granular genetic reports across all institutions [16].
Given the accelerated progression LFS patients harbor- ing brain tumors can experience; routine screening may play a role in early detection [18]. The most formal guid- ance in the literature is the Toronto protocol which suggests annual screening via MRI for brain tumors [17]. Given how quickly progression can occur some researchers have sug- gested an increase to a bi-annual screening program [17]. This is an evolving aspect of LFS research and has more recently reported attempts at liquid biopsy techniques as a more efficient means of tumor screening [17]. An argu- ment outlined by Ta et al., is that earlier detection via more frequent screening potentially reduces the incidence of sec- ondary effects of tumors such as seizures [17]. However, screening efforts may be limited by costs and logistic barri- ers associated with frequent MRIs.
While younger patients with LFS have a relatively increased risk of HGG formation compared with age matched cohorts, the relationship with advanced age and the development of HGG in this population follows a linear trajectory [19]. There may be an age threshold at which the interval screening increases [19].
Response to therapy
It has long been established that germline TP53 mutations are associated with an increased risk of adverse outcomes
[10]. A more complete understanding of the mechanisms driving treatment-tumor interactions with respect to the molecular background may be beneficial. WT TP53 as a negative regulator of MGMT gene expression has previ- ously been demonstrated, therefore it is proposed that mutant TP53 may result in overexpression of MGMT with resultant decline in the response to Temozolomide (TMZ) [1]. In support of this notion is the data demonstrating germ- line TP53 mutant glioma samples that have been associated with increased PI3K/AKT/mTOR signaling driving GBM drug resistance diminished effects of TMZ [1]. However, opposing data has reported that the absence of TP53 in an in vitro study of HGG tissue samples had increased sensitivity to TMZ through non-MGMT mechanisms [1].
IDH status has established a consistent role in predicting response to therapy and prognosis in HGG. Compared to sporadic HGG IDH WT in the setting of LFS has an asso- ciated favorable response to standard therapy compared to IDH mutants [14]. This dynamic reflects a clear difference in the molecular process of sporadic versus LFS HGGs. There has been a proposed increase in radiosensitivity in patients with germline mutations of TP53 in LFS [2].
A negative consequence is the vulnerability to develop- ing secondary malignancy resultant from radiation exposure [2]. Therefore, the risk benefit profile of patients undergo- ing radiation therapy for LFS associated HGGs ought to be especially balanced in younger patients [2]. While the theoretical risk of radiation induced malignancy is perva- sive across all hereditary tumor predisposition syndromes, clinical data in patients with LFS does not always sup- port this relationship. Hendrickson et al. analyzed a multi- institutional hereditary cancer database consisting of LFS patients and found no significant relationship between radi- ation therapy and development of secondary malignancy [20]. However, the authors of this study did report on two cases in which radiation was omitted from the treatment protocol following subtotal tumor resection with subse- quent local tumor recurrence [20]. This scenario exemplifies the role of adjuvant therapies alongside surgical resection and the clinical decision-making challenges in patients with known genetic instability. The quandary of radiation therapy in these patients is in part explained by the lack of granular data in the current literature. Bougeard et al. and Suri et al. both demonstrated subsequent tumor formation following radiation in LFS patients of 30% and 48% respec- tively [21, 22]. However, the studies lacked a clear defini- tion of secondary malignancy, and therefore a fraction of these reported outcomes may be better explained by recur- rent or progressive disease [20]. One of the strengths of the work performed by Hendrickson was the establishment of criteria for classifying secondary malignancy. As a result, in their work the authors demonstrated a 29% rate of local
tumor development following radiation, however none met the criteria for classification as secondary malignancy [20]. This data, albeit limited to this single study, does support the notion that the previously reported secondary malig- nancy rate may be skewed by recurrent or progressive dis- ease unrelated to the effects of radiation therapy. Finally, defining actionable mutation targets is a critical component of precision medicine. A hypermethylated TP53 promoter associated microRNA (miRNA34A) is one such potential target, which has demonstrated tumor initiation function in TP53 mutant hosts [2].
Future directions
Our review reveals that the boundaries of genetic variation within the LFS are not yet completely defined. Furthermore, the interface of molecular markers and treatment response is incompletely understood, although it appears to diverge from sporadic HGG. Finally, the natural history of HGG associated with LFS would benefit from more study to bet- ter inform an optimized strategy for routine screening pro- tocols. Screening ought to account for the risk of radiation induced malignancy versus prompt identification of tumors.
Many patients included in this review (Table 1) harbored genetic mutations reported in only 1-2% of cases of LFS associated HGG. Consistent with this there have only been 6 hotspot mutations demonstrated to account for 20% of HGGs associated with LFS, which leaves a great deal of genetic uncertainty and novelty accounting for the remain- ing 80%. This implies that our knowledge of the breadth and patterns of mutations in LFS needs continual updating and consolidation. If future investigations were able to pro- vide a simplified classification scheme, perhaps researchers would be better positioned to study the prognostic implica- tions of certain variant subsets. Additionally, the interaction between age and genetics cannot be understated. It has been reported that while identification of germline variants in younger patients with LFS is highly informative, the tumor biology in older patients may be a greater reflection of epi- genetic changes [23, 24].
Many of the previously reported cases corroborate the evidence provided by Kibe et al. in that typical mutational profiles seen in sporadic HGG often lack in LFS associated HGG [7]. Most commonly: PTEN mutations, loss of chro- mosome 7 and gain of chromosome 10 [7]. Additionally, given the theoretical risk of radiation induced secondary malignancy in patients with LFS, more tumor specific data ought to be reported. Previous multi-institutional efforts have been limited by heterogenous patient populations [20]. Furthermore, much of the data regarding this critical clini- cal problem are limited to breast cancer patients with LFS [20, 25, 26].
Lastly, there is still a great deal to be understood regard- ing optimal surveillance screening. Initially, most tumors are identified through an institutional LFS screening pro- tocol. Patients in this cohort may benefit from a more stan- dardized approach, and research on best practices would also benefit from a pre-defined standard screening protocol. Furthermore, if there are specific genetic signatures associ- ated with rapid progression what is the ideal imaging follow up and initiation of adjuvant therapies like EBRT and TMZ.
Conclusion
LFS associated HGG is a scarcely reported phenomenon and demonstrates high levels of genetic heterogeneity and unpredictable outcomes to standard therpies. There is much uncertainty surrounding the extent of gene variation in this group and the dynamics between specific genetic events and response to a variety of therapies. Finally, the implications for screening and disease monitoring are not fully delin- eated. In general, germline mutation of TP53 may play an important role in both sporadic and familial tumor types, particularly the response to TMZ. Unfortunately, relative to IDH and MGMT the evidence of the role for TP53 in HGG is lacking. Pooled data sets and larger cohort stud- ies will be necessary to unify the literature and advance our understanding.
Acknowledgements None.
Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [T.K], [R.V], [V.Y], [M.P], [M.S], [R.W], [S.K], and [J.H]. The first draft of the manuscript was written by [T.K] and all authors revised the following versions of the manuscript. All authors read and approved the final manuscript.
Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Data availability No datasets were generated or analysed during the current study.
Declarations
Ethical approval Not applicable.
Competing interests Matthew J. Shepard, MD is a consultant for GT Medical Inc.
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