Abstract
Background
High-grade diffuse gliomas in adults are common malignant primary tumors of the central nervous system. The association with Lynch syndrome (LS) is documented but remains under-researched. However, there are implications for prevention, genetic counseling, and therapeutic approaches. The objective of this study is to conduct a descriptive cohort of patients with high-grade glial tumors in the context of LS.
Methods
We included adult patients with glioblastoma (GBM) or grade 4 astrocytoma (WHO 2021 classification) associated with LS, diagnosed at Lille University Hospital or Valenciennes Hospital between 2014 and 2022. We retrospectively collected clinical, radiological, histopathological, molecular, and therapeutic data.
Results
We included 6 GBM cases with a median age of 58.7 years (IQR 32.4-63.3). Five cases had MSH2 mutations, and one had PMS2 mutation. In one case, MMR protein expression was preserved, and the RER phenotype showed low microsatellite instability. Loss of ATRX expression, overexpression of p53, and giant cells were observed in 50%, 83%, and 66% of cases, respectively. TP53 mutations were found in all cases, and PTEN mutations in 4 cases. Immunotherapy was given to two cases. The 24-month overall survival rate was 50%.
Conclusions
GBMs associated with LS exhibit specific histopathological and molecular biology characteristics that may guide syndrome-related research. These tumors could represent a particular subclassification, potentially leading to specific therapies such as immunotherapy. We propose with a review of case in the literature an algorithm for investigating LS upon discovering a GBM. These exploratory results need to be confirmed by a larger cohort.
Keywords: glioblastoma, glioma, Lynch syndrome, MMR
Key Points:
- Glioblastomas associated with Lynch syndrome are a specific entity.
- Identification through clinical, pathological, and molecular criteria.
- Potential therapeutic implications with specialized management.
Importance of the Study.
Our study on high-grade gliomas associated with Lynch syndrome aims to describe this little-known specific population, based on one of the largest cohorts in the literature, along with a review of other reported cases. This allowed us to propose a decision-making algorithm based on clinical, pathological, and molecular biology criteria to better identify patients at diagnosis. Furthermore, this specific subgroup of patients could benefit from targeted treatments.
The association between glioma and Lynch syndrome (LS) was first described by Turcot et al. in 1959.1 Later studies confirmed an increased risk of glial tumors among LS patient, with 2% to 3.3% affected, compared with 0.47% in the general population.2,3 A study by Therkildsen et al.4 specifically associated congenital MSH2 mutation (2.5%) with increased brain tumors, particularly glioblastomas (GBMs), comprising 56% of cases.
Diagnosing LS typically begins with microsatellite instability (MSI), followed by testing for the congenital mutation, guided by the revised Bethesda criteria.5 However, Latham et al.6 found these criteria insufficient for MSI testing in 45% of LS cases, highlighting a lack of sensitivity in the Bethesda criteria.
Recent therapeutic studies have demonstrated the potential of immunotherapy, particularly PD1 immune checkpoint inhibitors, in managing tumors, including noncolorectal ones, that have mismatch repair (MMR) system deficiencies.7–9 The rationale for this therapy is increased immune activity within these tumors, due to a higher tumoral mutational burden (TMB).10
In the context of the association between glioma and LS, several studies have highlighted the presence of high-grade glial tumors (GBMs and grade 4 astrocytomas) with a hypermutated profile due to somatic mutations in the MMR system.11–13 As mentioned earlier, these tumors may be more responsive to immunotherapy, although data on this topic are limited and primarily come from case studies. Furthermore, the hypermutated profile could confer resistance to Temozolomide (TMZ), raising questions about the use of this drug in the Stupp protocol as a first-line treatment.14,15
Therefore, the association between glioma and LS remains poorly understood and is rarely described in the literature. There are no specific criteria within gliomas to guide the search for LS. However, there are important clinical implications for diagnosing LS, particularly regarding the recommendation of prophylactic and surveillance measures for patients and their relatives.16 There are also therapeutic implications for patients, including the potential reconsideration of TMZ use and the possibility of proposing immunotherapy.
Given this background, the primary objective of this study was to identify clinical, biological, radiological, histopathological, and molecular biology criteria that could indicate a constitutional alteration of an MMR gene, warranting referral for oncogenetic consultation of patients with high-grade glial tumors in the context of LS.
The secondary objectives of this study are to evaluate the tumor response to standard treatment and immunotherapy; and to conduct a literature review of cases meeting the inclusion criteria of our study.
Materials and Methods
Study population
The study included patients over 18 diagnosed with GBM or grade 4 astrocytoma per WHO 2021 criteria, with possible LS. Diagnoses were made at Lille University Hospital or Valenciennes Hospital from 2014 to 2022. Patients met criteria for oncogenetic referral if diagnosed with GBM under 30 and had a personal or first-degree or a second-degree family history of LS-associated cancers. The study was registered with CNIL (Number of registration DEC24-027), and patients’ nonopposition was confirmed by mailed information letters.
Data
For all patients data were collected retrospectively from the electronic records of Lille University Hospital or Valenciennes Hospital. Data collection was censored on April 30, 2024. Progression-free survival and overall survival data were collected based on reassessment imaging (with a maximum interval of 3 months) and clinical examination analyzed according to RANO criteria.
For all patients in the cohort, a morphological analysis was performed on a sample from the initial brain tumor resection after hematoxylin and eosin staining. Immunohistochemistry (IHC) was conducted for all patients to analyze IDH1R132H, ATRX, and p53. All slides were reviewed by an experienced pathologist specializing in neuro-oncology member of RENOCLIP.
For all patients, we performed: 1) A molecular karyotype using a CGH Array; 2) the RER phenotype was determined through the analysis of a Hexaplex panel of microsatellite markers. If at least 2 markers were unstable, high microsatellite instability (MSI-H) was confirmed. If only 1 marker was unstable, we concluded low microsatellite instability (MSI-L); 3) a search for hypermethylation of the MGMT gene promoter; 4) a next-generation sequencing (the list of gene exons analyzed in this panel is available in Datasupp 1); and 5) a TMB analysis: the positivity was set at 10 mutations per megabase, in accordance with literature data.17–19
For all patients, the diagnosis of LS was confirmed by the identification of a pathogenic germline mutation through constitutional genetic testing.
Statistical analysis
Survival data were represented using a Kaplan–Meier survival curve. Medians and means with standard deviation were provided with a 95% confidence interval, using XLSTAT software.
Results
We found 6 cases of GBM associated with LS diagnosed between January 2015 and March 2022. No patients with the association of grade 4 astrocytoma and LS were found during the study period.
The clinical, radiological, and genetic data of our cohort are summarized in Figure 3. The initial imaging is presented in Figure 1. The median age of patient at diagnosis was 58.7 years (interquartile range IQR [32.4-63.3]). All patients had an WHO score of 2 or lower (100%). Two cases (33%) did not have a personal or family history of tumors associated with the LS spectrum.
Figure 3.
Main clinical, radiological, genetic, pathological, and molecular biology characteristics of the 6 cases. The color legend is displayed to the right of the figure.
Figure 1.
Illustration of the initial radiological data in magnetic resonance imaging (MRI) for the 6 cases (T2* = magnetic susceptibility sequence for hemorrhagic changes): Case 1: A 21-y-old men with right frontal GBM; Case 2: A 25-y-old men with right parieto-temporo-occipital GBM; Case 3: A 62-y-old men with left temporal GBM; Case 4: A 65-y-old men with right occipital hemorrhagic GBM; Case 5: A 54-y-old women with right frontal GBM; Case 6: A 63-y-old men with right posterior temporal GBM.
The anatomical and immunohistochemical data of GBM cases associated with LS in our cohort are summarized in Figure 3. Photographs of the initial tumor slides are presented in Figure 2. Notably, 66% of cases showed the presence of giant cells, 83% showed overexpression of p53 in IHC, and 50% showed loss of ATRX expression in IHC. Additionally, all MMR proteins were preserved in 1 case (17%).
Figure 2.
Illustration of the pathology slides for the 6 cases: Case 1: A 21-y-old GBM with absence expression of ATRX and MSH2; Case 2: A 25-y-old GBM with preserved expression of MLH1, PMS2, and absence expression of ATRX; Case 3: A 62-y-old GBM with loss of expression MSH2 end MSH6; Case 4: A 65-y-old GBM with loss of expression MSH2 and MSH6; Case 5: A 54-y-old GBM with loss of expression MSH2 and MSH6; Case 6: A 63-y-old GBM with loss of expression ATRX, MSH2, and MSH6.
The molecular biology data for the cohort of cases with GBM associated with LS are summarized in Figure 3. These finding compared with clinical, radiological, genetic, and pathological data revealed several key molecular characteristics: 1) the absence of trisomy 7 associated with monosomy 10 in all tumors of the cohort; 2) the presence of a molecular alteration in the TP53 gene in 100% of cases (double mutation in 66% of cases), with a loss of function of the p53 protein in all cases; 3) the presence of a molecular alteration in the PTEN gene in 66% of cases, leading to loss of function in 50% of cases and a truncated protein in 50% of cases, 4) the presence of a molecular alteration in the PIK3CA gene in 33% of cases, resulting in a constitutively activated protein; and 5) the absence of EGFR amplification in the entire cohort.
Regarding MSI in molecular biology, as assessed by the panel of 6 markers, 5 cases showed an MSI-H status (at least 2 markers) and 1 case showed an MSI-L status (1 marker only).
Concerning the mutational burden, 83% of cases showed a high TMB, with a median of 16.2 mutations per megabase (mut/Mb) (IQR [13.8-24.2]).
Regarding methylome analysis (performed only for case 6), according to version 12.8 of the DFKZ database, this classified the tumor as a high-grade neuroepithelial diffuse glioma in adults, with no further diagnostic specification possible.
Therapeutic data for the cohort of LS associated GBM cases are summarized in Figure 4.
Figure 4.
Treatments undertaken since diagnosis with the associated survival for the 6 cases.
All patients underwent initial surgical resection, which was complete for cases 1 to 5 (83% of cases) and partial for case 6 (17% of cases). All patients then received the Stupp protocol. Only case 3 experienced a premature interruption of this concomitant radio-chemotherapy after 52 Grays. Dose reduction to 150 mg/m² was observed starting from the third cycle for case 1 and from the fourth cycle for case 5 due to grade 3 thrombocytopenia.
Among the 6 cases, 4 experienced a recurrence during follow-up, 1 patient died early during the Stupp protocol, and the last patient has not yet experienced a recurrence following the Stupp protocol. Cases 1 and 5 were able to receive immunotherapy.
For case 1, immunotherapy with Durvalumab at a dose of 10 mg/kg every 3 weeks was introduced during the second recurrence. The patient had previously received Zotiraciclib associated with prior surgery at the time of the first recurrence. The progression-free survival under immunotherapy was 89 days, with good tolerance noted.
For case 5, immunotherapy was introduced at the first recurrence, without possible prior surgery, using Pembrolizumab at 200 mg every 3 weeks. The progression-free survival for this line of treatment was 118 days, with good tolerance noted.
The 24-month overall survival rate for GBMs associated with LS in the study is 3 out of 6 cases (50%). The 24-month overall survival rate in case of high TMB is 3 out of 5 cases (60%).
Discussion
We report 6 cases of GBMs associated with LS, with a median age of 58.7 years (mean of 48.7 years), younger than typical GBM patients. This may reflect the genetic predisposition of LS patients to develop multiple tumors early in life.20 In our cohort, TP53 mutations were present in all cases, and PTEN mutation in 66%, which is higher than in nonsyndromic GBMs, where TP53 and PTEN mutations are seen in 19-27% and 24-26% of cases, respectively.21 None of our patients had EGFR amplification or common chromosomal abnormalities (gain of chromosome 7 and loss of chromosome 10), typical in GBMs. Histologically, giant cells were present in 66% of cases; IHC showed loss of ATRX expression in 50% of cases and overexpression of p53 in 83% of cases.
A new entity?
These results are consistent with other literature finding, particularly with Hadad et al.18 who studied 459 GBMs and identified a distinct hypermutated subset (2%), characterized by MMR gene inactivation, particularly in LS patients with germline mutations. This subset exhibited younger onset (median age 50 vs 63 years), low rates of TERT promoter mutations (11%), no EGFR amplification (0%), and no cases with gain of chromosome 7 and loss of chromosome 10. This subgroup was associated with other molecular signatures, including ATRX mutation (56%), TP53 mutation (89%), NF1 mutation (56%), PTEN mutation (78%), and SETD2 mutation (67%). Histology often showed giant cells. The DNA methylation signature of these tumors was closer to the “diffuse high-grade pediatric glioma, RTK1 subtype, subclass A.” These findings suggest the existence of a specific tumor subtype within these high-grade, IDH wild-type glial tumors, termed “De novo Glioblastoma with MMR System Deficiency, IDH Wild-Type.”18 In our study, methylome analysis on one patient classified as an adult diffuse glioma without concordance for a high-grade IDH wild-type diffuse glioma which may reflect underclassification of LS-associated tumors. Systematic methylome analysis for this type of tumor would be of interest.
Benusiglio et al. also reported a subset of GBMs with MMR deficiency and common features, including TP53 and NF1 mutations, in a cohort of 9 GBMs patients (5 with LS). A younger average age at diagnosis (35 years) was noted.11
Another descriptive study by Kim et al. also found that GBMs with MMR deficiency (n = 9), including some with LS (n = 5/9), had increased TP53 and NF1 mutations and PDGFRA amplification. PIK3CA mutations were also highlighted in this group. All LS cases had MSI-H status.22
Therapy and microenvironment
MMR deficiency has possible therapeutic implications, particularly with TMZ and immunotherapy. In our study, all patients received TMZ as a first-line treatment with the Stupp protocol. TMZ is an alkylating agent that methylates DNA, activating the MMR system to induce double-strand breaks and apoptosis. However, in MMR-deficient gliomas, cells survive this damage, accumulating mutations and developing a hypermutated profile, leading to TMZ resistance. Lomustine, a bifunctional agent, does not face similar resistance in MMR-deficient cells.15,23
Ex vivo studies with MMR-deficient glioma cells confirm this pattern, showing resistance to TMZ but sensitivity to Lomustine.13 It is therefore necessary to question the relevance of using TMZ as part of the Stupp protocol in this specific population.
In our study, 2 patients received immunotherapy (Pembrolizumab or Durvalumab) at recurrence, with limited benefit and early progression. Conflicting data are also reported in the literature, such as the study by Hodges et al. link a high mutational burden to MMR protein loss but found no markers, such as increased CD8+ T-cell influx, to suggest improved immunotherapy outcomes in GBMs. Notably, nearly half of the GBMs in this study were recurrences, potentially reducing statistical power.17
Rare cases of immunotherapy use in GBMs associated with LS have been reported in the literature. Nivolumab combined with radiotherapy is proposed for recurrent GBMs, reportedly leading to a 20-months survival after recurrence.24 Indeed, radiotherapy might have a synergistic effect with immunotherapy by inducing a stronger immune response through increased presentation of tumor antigens. This has been demonstrated in murine glioma models and showing the presence of long-term survivors with increased infiltration of cytotoxic CD8+ T lymphocytes.25 Dual immunotherapy (anti-PD-L1 and anti-CTLA4) combined with radiotherapy could be a promising approach for MMR-deficient GBMs.26
Response variability might relate to differing major histocompatibility complex class 1 expression, essential for antigen presentation, which can be lost due to mutations.27 Another limitation of the effectiveness of immunotherapy could be related to the mode of administration. Further studies are needed to determine the prognostic value of this parameter and its implications for immunotherapy.
No studies have tested PD-1 immunotherapy as first-line treatment for MMR-deficient GBMs. Further research is needed to identify predictive biomarkers for immunotherapy response, with mutational burden analysis.
TMB representing the number of somatic mutations in tumors is linked to MMR deficiency. In our study, 83% of patients showed high TMB (average 29.2 mut/Mb), similar to Richardson et al., who reported much higher TMB in MMR-deficient gliomas: 84.9 mut/Mb in astrocytomas and 131.9 in GBMs, compared with significantly lower TMB in MMR-proficient tumors. Acquired MMR deficiency, often following TMZ treatment, appears to drive increased TMB, supporting a hypermutated phenotype in MMR-deficient gliomas.19,28,29
Ex vivo models also confirm that MMR deficiency and TMZ treatment leads to a hypermutated profile, reducing survival benefits compared with hypermutated cancers such as colorectal cancer. This may stem from the lower immune response in the central nervous system, with limited lymphocytic infiltration and low-quality antigens across multiple tumor subclones.13
Moreover, lymphocytic infiltration, particularly by CD8+ T cells rather than CD4+ T cells, associated with better prognosis. In contrast, PD-L1 expression, often used as a biomarker for immunotherapy eligibility in other cancers, may not be reliable in gliomas. High PD-L1 expression is associated with higher tumor grade and poorer survival but does not predict improved immunotherapy responses, possibly due to therapy-resistant subclones and neoantigens unrecognized by the immune system.30,31
In our study, the 24-month overall survival rate for GBMs associated with LS is 3 out of 6 cases (50%), which may have improved survival compared with standard GBMs, aligning with findings like those of Hadad et al., which reported a median survival of 36.6 months in GBMs associated with LS.18 The 24-month overall survival rate for high TMB cases in the study is 60%, which appears particularly high in this population. However, this result is based on a small sample size (5 cases), including 2 long-term survivors, and currently lacks supporting data in the literature, warranting confirmation in future studies.
Criteria for referral to oncogenetics for LS
In our study, 5 cases showed a loss of expression of at least 1 MMR protein, with an MSI-H status. The remaining case did not show a loss of MMR protein expression, and its molecular biology status was MSI-L. This highlights the limitations of IHC sensitivity.
Current recommendations for diagnosing MMR deficiency are based on colorectal cancer studies, advising dual testing with IHC and molecular biology (PCR-based MSI testing). For brain tumors, this dual method is less sensitive. Therefore, alternative techniques, such as using long mononucleotide repeat markers and an 8-marker panel, have been developed. This method shows better sensitivity, especially for noncolorectal tumors, though comparison with healthy tissue is necessary.32
Based on our findings and existing literature, we recommend a systematic MMR deficiency assessment in suspected LS-associated GBM cases using both IHC and molecular biology with the Hexaplex method.
In our study, patients referred for genetic counseling for suspected LS met criteria based on age, personal or family history of LS-related tumors, or multiple family histories of cancers in the LS spectrum. However, these criteria lack of sensitivity.6
Similarly, Benusiglio et al. identified GBM cases associated with LS in patients under 50 with family histories of LS-related cancers, despite lacking a personal or first-degree family history. Their study suggested that systematic LS screening should be implemented for GBM patients under 50 with relevant family histories or histological markers such as p53 overexpression, ATRX loss, and giant cells.11
Our findings, supported by previous studies, suggest that LS referral criteria should incorporate both clinical and histo-molecular factors to improve sensitivity.11,18,22 The current age-based criterion is inadequate since LS-associated GBM patients tend to be younger than the general GBM population, with a median age closer to 50. Revised criteria could include histo-molecular factors such as TP53 or PTEN mutations, giant cells, p53 overexpression, ATRX loss, and a high TMB. We propose a decision-making algorithm (Figure 5) combining clinical and histo-molecular criteria may better identify LS-associated GBM, requiring validation in future studies.
Figure 5.
Proposed decision tree for exploring Lynch syndrome in the context of a GBM according to the 2021 WHO classification.
Strenghts and limitation of our study
This study’s strengths include one of the largest cohorts of patients with high-grade glioma associated with LS and its multicentric design with minimal missing data. A monocentric analysis of pathology and molecular biology ensures consistent diagnostic criteria, complemented by a comprehensive literature review. However, limitations include the retrospective nature of data collection, which may introduce collection bias. Another limitation of our study is the potential for selection bias. In our institution, the investigation for LS in the context of GBM is guided by specific criteria, namely diagnosis of GBM before the age of 30, or a personal or first-degree family history of tumors within the broader LS spectrum. It would therefore be of interest to broaden the criteria for LS screening in future studies in order to minimize potential selection bias. Additionally, the small cohort size limits the scope of some analyses, particularly survival related data.
Conclusion
Based on comprehensive data from both literature and our study, GBMs associated with LS exhibit specific histopathological and molecular biology characteristics that may guide syndrome-related research. Further exploration of the association between high-grade gliomas and LS is crucial. This could lead to advancements in patient care, including innovative therapies to extend life expectancy and genetic counseling to support affected families. Comparing high-grade gliomas with other MSI tumors, such as colorectal and endometrial cancers, could improve understanding of their pathogenesis. Systematically investigating MMR deficiency in glioma patients and referring them for genetic counseling using a decision-making algorithm is essential. Establishing an international registry would enable larger cohorts, enhancing research and improving patient management.
Supplementary Material
Contributor Information
Hugo Duprez, Department of Neuro Oncology, CHU Lille, 59000 Lille, France.
Apolline Monfilliette, Department of Neuro Oncology, CHU Lille, 59000 Lille, France.
Marie Csanyi, Institute of Pathology, CHU Lille, 59000 Lille, France.
Claude-Alain Maurage, Institute of Pathology, CHU Lille, 59000 Lille, France.
Fabienne Escande, Department of Biochemistry and Molecular Biology, CHU Lille, 59000 Lille, France.
Afane Brahimi, Department of Clinical Genetics, CHU Lille, 59000 Lille, France.
Anthony Turpin, Department of Medical Oncology, CHU Lille, 59000 Lille, France.
Nicolas Reyns, Department of Neurosurgery, CHU Lille, 59000 Lille, France.
Luc Defebvre, Department of Neuro Oncology, CHU Lille, 59000 Lille, France.
Enora Vauleon, Department of Neuro Oncology, CHU Lille, 59000 Lille, France.
Acknowledgements
Thanks to the Institute of Pathology, the Department of Biochemistry and Molecular Biology, and the Department of Clinical Genetics at the Lille University Hospital for their assistance in this work. This is an observational study, and patient nonopposition was sought in accordance with the legislation. Approval was granted by CNIL (Number of registration DEC24-027).
Conflict of interest statement.
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
A.T. declare consulting fees for Servier, AstraZeneca, BMS, Nordige, Pierre Fabre, Incytea, and Amgen; Payment for presentation by BMS; Support for meeting by Servier, AstraZeneca, Pierre Fabre, and Merck. Others authors have no relevant financial or nonfinancial interests to disclose.
The first draft of the manuscript was written by H.D., the illustration was created by H.D., and all authors commented on previous versions of the manuscript.
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
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