Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).
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ABSTRACT:
SUBMITTER: Briggs M
PROVIDER: S-EPMC10099894 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).
Briggs Mayen M Das Anirban A Firth Helen H Levine Adrian A Sánchez-Ramírez Santiago S Negm Logine L Ercan Ayse B AB Chung Jill J Bianchi Vanessa V Jalloh Ibrahim I Phyu Poe P Thorp Nicky N Grundy Richard G RG Hawkins Cynthia C Trotman Jamie J Tarpey Patrick P Tabori Uri U Allinson Kieren K Murray Matthew J MJ
Neuropathology and applied neurobiology 20221118 1
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Project description:Constitutional mismatch repair deficiency (CMMRD) is a cancer predisposition due to biallelic mutations in one of the mismatch repair (MMR) genes associated with early onset of cancers, especially high-grade gliomas. Our aim was to decipher the molecular specificities of these gliomas. Clinical, histopathological, and whole exome sequencing data were analyzed in 12 children with genetically proven CMMRD and a high-grade glioma. PDL1 expression was present in immunohistochemistry in 50% of the samples. In 9 patients, the glioma harbored an ultra-hypermutated phenotype (104-635 coding single nucleotide variants (SNV) per Mb, median 204). Driver mutations in POLE and POLD1 exonuclease domains were described for 8 and 1 patients respectively and were always present in the mutation burst with the highest variant allele frequency (VAF). The mutational signatures were dominated by MMR-related ones and similar in the different mutation bursts of a same patient without subsequent enrichment of the mutation signatures with POL-driven ones. Median number of coding SNV with VAF above one of the driving polymerase mutation per Mb was 57 (17-191). Our findings suggest that somatic polymerase alterations does not entirely explain the ultra-hypermutant phenotype. SETD2, TP53, NF1, EPHB2, PRKDC, and DICER1 genes were frequently mutated with higher VAF than the deleterious somatic polymerase mutation. CMMRD-associated gliomas have a specific oncogenesis that does not involve usual pathways and mutations seen in sporadic pediatric or adult glioblastomas. Frequent alterations in other pathways such as MAPK may suggest the use of other targeted therapies along with PD1 inhibitors.
| S-EPMC11372297 | biostudies-literature
Project description:Abstract BACKGROUND Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome (OMIM#276300) due to biallelic germline mutations in MMR genes, leading to a broad spectrum of childhood malignancies including brain, hematologic and colorectal cancers associated with café-au-lait macules (CALM). METHODS Malignant brain tumors (BT) were reported in 48/78 patients (10 countries), registered in the C4MMRD database. RESULTS Overall, 55 BT (47 high-grade gliomas (HGG) and 8 embryonal tumors) were diagnosed in 48 patients between 1988-2017. Median age at the first BT was 9.1y (1.1-40.6) with 8 patients over 18y. Twenty-eight patients developed multiple malignancies (including 17 before the BT). Twenty/37 families were consanguineous. All patients had biallelic germline mutations in MMR genes: PMS2 (26pts), MSH6 (10pts), MSH2 (7pts) and MLH1 (5pts). All patients with available cutaneous data but one had CALM. In addition several patients presented developmental brain anomalies. Most patients received standard treatment before immunotherapy era, without unusual treatment-related toxicity. Median survival after the first BT was 2y. Five-year overall-survival was 23% (95%-CI, 12-41) and 45% (95%-CI, 17-76) for HGG and embryonal tumors respectively. Ten patients are alive (7 HGG and 3 medulloblastomas) at last follow-up. Among the 38 deaths, 33 patients died because of their BT (first BT=28, second BT=5) and 5 of other cancers. CONCLUSION Despite a high risk of multiple malignancies, this series suggests that some patients may be long-term survivors. Prognosis could be improved by early recognition of this rare condition leading to more specific treatments including immunotherapy and screening for second malignancies.
| S-EPMC6012064 | biostudies-literature
Project description:Ependymomas are neuroepithelial tumors of the central nervous system (CNS), presenting in both adults and children but accounting for almost 10% of all pediatric CNS tumors and up to 30% of CNS tumors in children under 3 years (Bouffet et al., 2009; McGuire et al., 2009; Rodriguez et al., 2009). In children, most ependymomas arise in the posterior fossa, while most adult ependymomas present around the lower spinal cord and spinal nerve roots. Ependymomas display a wide range of morphological features, and several variants are listed in the World Health Organization (WHO) classification (Ellison et al., 2016). These variants are assigned to three WHO grades (I-III), but the clinical utility of this classification is acknowledged to be limited (Ellison et al., 2011). An increasing understanding of the genomic landscape of ependymoma and the discovery of distinct molecular groups by DNA methylation or gene expression profiling have begun to refine approaches to disease classification and prognostication, but have yet to be translated into clinical routine (Hoffman et al., 2014; Mack et al., 2014; Pajtler et al., 2017; Pajtler et al., 2015; Parker et al., 2014; Wani et al., 2012; Witt et al., 2011). Our comprehensive study of DNA methylation profiling across the entire disease demonstrated three molecular groups for each major anatomic compartment: supratentorial (ST), posterior fossa (PF), and spinal (SP) (Pajtler et al., 2015). In the ST compartment, two molecular groups (ST-EPN-RELA and ST-EPN-YAP1) align with tumors harboring specific genetic alterations, RELA and YAP1 fusion genes, which were initially discovered in a whole genome sequencing study (Parker et al., 2014). Among PF ependymomas, two of three molecular groups, PFA (PF-EPN-A) and PFB (PF-EPN-B), account for nearly all tumors; PF-SE tumors are rare, generally showing the morphology of a subependymoma (Pajtler et al., 2015). PFA tumors are found mainly in infants and young children (median age ≈ 3yrs) and have a relatively poor outcome, while PFB tumors are generally found in young adults (median age ≈ 30yrs) and are associated with a better prognosis (Pajtler et al., 2015; Witt et al., 2011). PFA tumors show few copy number alterations (CNAs), while PFB tumors harbor multiple CNAs that tend to affect entire chromosomes. While recurrent structural variants (SVs) are found in ST ependymomas, recurrent SVs or other mutations, such as single nucleotide variants (SNVs) and insertions or deletions (indels), have not been identified in PF ependymomas to date (Mack et al., 2014; Parker et al., 2014).
2018-06-26 | GSE104210 | GEO
Project description:BackgroundConstitutional mismatch repair deficiency syndrome results from bi-allelic inheritance of mutations affecting the key DNA mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. Individuals with bi-allelic mutations have a dysfunctional mismatch repair system from birth; as a result, constitutional mismatch repair deficiency syndrome is characterised by early onset malignancies. Fewer than 150 cases have been reported in the literature over the past 20 years. This is the first report of the founder PMS2 mutation - NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11 and its associated cancers in this family.Case presentationThe proband is 30 years old and is alive today. She is of Pakistani ethnic origin and a product of consanguinity. She initially presented aged 24 with painless bleeding per-rectum from colorectal polyps and was referred to clinical genetics. Clinical examination revealed two café-au-lait lesions, lichen planus, and a dermoid cyst. Her sister had been diagnosed in childhood with an aggressive brain tumour followed by colorectal cancer. During follow up, the proband developed 37 colorectal adenomatous polyps, synchronous ovarian and endometrial adenocarcinomas, and ultimately a metachronous gastric adenocarcinoma. DNA sequencing of peripheral lymphocytes revealed a bi-allelic inheritance of the PMS2 mutation NM_000535.5:c.1500del (p.Val501TrpfsTer94) in exon 11. Ovarian tumour tissue demonstrated low microsatellite instability. To date, she has had a total abdominal hysterectomy, bilateral salpingo-oophorectomy, and a total gastrectomy. Aspirin and oestrogen-only hormone replacement therapy provide some chemoprophylaxis and manage postmenopausal symptoms, respectively. An 18-monthly colonoscopy surveillance programme has led to the excision of three high-grade dysplastic colorectal tubular adenomatous polyps. The proband's family pedigree displays multiple relatives with cancers including a likely case of 'true' Turcot syndrome.ConclusionsConstitutional mismatch repair deficiency syndrome should be considered in patients who present with early onset cancer, a strong family history of cancer, and cutaneous features resembling neurofibromatosis type I. Immunohistochemistry analysis of tumour and normal tissue is sensitive and specific for identifying patients with mismatch repair deficiency and should direct DNA sequencing of lymphocytic tissue to establish a diagnosis. Microsatellite instability status appears to be of little value in identifying patients who may have constitutional mismatch repair deficiency syndrome.
| S-EPMC5381022 | biostudies-literature
Project description:Better understanding of ependymoma (EPN) biology at relapse is needed to improve therapy at this critical event. Convincing data exist defining transcriptionally distinct posterior fossa (PF) sub-groups A and B at diagnosis. The clinical and biological consequence of these sub-groups at recurrence has not yet been defined. Genome and transcriptome microarray profiles and clinical variables of matched primary and first recurrent PF EPN pairs were used to identify biologically distinct patterns of progression between EPN sub-groups at recurrence. Key findings were validated by histology and immune function assays. Transcriptomic profiles were partially conserved at recurrence. However, 4 of 14 paired samples changed sub-groups at recurrence, and significant sub-group-specific transcriptomic changes between primary and recurrent tumors were identified, which were predominantly immune-related. Further examination revealed that Group A primary tumors harbor an immune gene signature and cellular functionality consistent with an immunosuppressive phenotype associated with tissue remodeling and wound healing. Conversely, Group B tumors develop an adaptive, antigen-specific immune response signature and increased T-cell infiltration at recurrence. Clinical distinctions between sub-groups become more apparent after first recurrence. Group A tumors were more often sub-totally resected and had a significantly shorter time to subsequent progression and worse overall survival. Minimal tumor-specific genomic changes were observed for either PF Groups A or B at recurrence. Molecular sub-groups of PF EPN convey distinct immunobiologic signatures at diagnosis and recurrence, providing potential biologic rationale to their disparate clinical outcomes. Immunotherapeutic approaches may be warranted, particularly in Group A PF EPN.
| S-EPMC3988227 | biostudies-literature
Project description:Genomewide DNA methylation array profiling of nine posterior fossa ependymomas harboring activating mutations in ACVR1. Two samples clustered with the PFA subtype and demonstrated H3K27me3 loss by immunohistochemistry, while the remaining 7 showed retained H3K27me3 and formed a methylation cluster distinct from other ependymal tumors. For these previsouly unpublished cases, the Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue.
2022-05-01 | GSE196013 | GEO
Project description:Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.
| S-EPMC6105278 | biostudies-literature
Project description:PurposeImaging descriptions of posterior fossa ependymoma in children have focused on magnetic resonance imaging (MRI) signal and local anatomic relationships with imaging location only recently used to classify these neoplasms. We developed a quantitative method for analyzing the location of ependymoma in the posterior fossa, tested its effectiveness in distinguishing groups of tumors, and examined potential associations of distinct tumor groups with treatment and prognostic factors.MethodsPre-operative MRI examinations of the brain for 38 children with histopathologically proven posterior fossa ependymoma were analyzed. Tumor margin contours and anatomic landmarks were manually marked and used to calculate the centroid of each tumor. Landmarks were used to calculate a transformation to align, scale, and rotate each patient's image coordinates to a common coordinate space. Hierarchical cluster analysis of the location and morphological variables was performed to detect multivariate patterns in tumor characteristics. The ependymomas were also characterized as "central" or "lateral" based on published radiological criteria. Therapeutic details and demographic, recurrence, and survival information were obtained from medical records and analyzed with the tumor location and morphology to identify prognostic tumor characteristics.ResultsCluster analysis yielded two distinct tumor groups based on centroid location The cluster groups were associated with differences in PFS (p = .044), "central" vs. "lateral" radiological designation (p = .035), and marginally associated with multiple operative interventions (p = .064).ConclusionsPosterior fossa ependymoma can be objectively classified based on quantitative analysis of tumor location, and these classifications are associated with prognostic and treatment factors.
| S-EPMC4967400 | biostudies-literature
Project description:Background5-Hydroxymethylcytosine (5hmC) is a novel epigenetic mark and may be involved in the mechanisms of tumorigenesis and malignant transformation. However, the role of 5hmC in ependymoma, the third most common brain tumor in children, remains unclear. The aim of this study sought to identify the characterization of 5hmC levels in pediatric posterior fossa ependymoma and to evaluate whether 5hmC levels could be a potential factor to predict clinical outcomes.ResultsOur results showed that 5hmC levels were globally decreased in posterior fossa ependymoma compared with normal cerebellum tissues (P < 0.001). Group A posterior fossa ependymomas had higher 5hmC levels than group B tumors (P = 0.007). Moreover, 5hmC levels positively correlated with Ki-67 index in posterior fossa ependymoma (r = 0.428, P = 0.003). Multivariate Cox hazards model revealed that patients with high 5hmC levels (> 0.102%) had worse PFS and OS than patients with lower 5hmC levels (< 0.102%) (PFS: HR = 3.014; 95% CI, 1.040-8.738; P = 0.042; OS: HR = 2.788; 95% CI, 0.974-7.982; P = 0.047).ConclusionsOur findings suggest that loss of 5hmC is an epigenetic hallmark for pediatric posterior fossa ependymoma. 5hmC levels may represent a potential biomarker to predict prognosis in children with posterior fossa ependymoma.
| S-EPMC6988368 | biostudies-literature
Project description:ACVR1-mutant posterior fossa ependymoma
| PRJNA802906 | ENA