Germline Biallelic Mismatch Repair Deficiency in Childhood Glioblastoma and Implications for Clinical Management
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.344608
Source of Support: None, Conflict of Interest: None
Keywords: CMMRD, hypermutation, immunotherapy
Brain tumors are the second-most common malignancy and the leading cause of cancer-related death in <19 years of age. Pediatric high-grade glioma (PHGG), comprising 8%–12%, includes anaplastic astrocytoma (WHO grade III) and glioblastoma (grade IV). They have a dismal 5-year survival (<20%) despite complete resection, radiation, and chemotherapy. PHGG is biologically distinct from adult HGG. A significant proportion is driven by histone mutations; IDH-1 mutations are seen in adolescents as the lower tail of the adult spectrum. Many are associated with cancer-predisposing conditions (CPS) such as Li–Fraumeni, neurofibromatosis type-I, and constitutional mismatch repair deficiency (CMMRD) syndromes. CMMRD is a fatal CPS simultaneously predisposing to PHGG, embryonal, colorectal, and haemato-lymphoid malignancies, caused by germline mutations in the DNA-mismatch repair (MMR: MLH1, MSH2, MSH6, PMS2, EPCAM) genes. We report the direct clinical impact of diagnosis, comprehensive genomic analysis, and challenges during PD-1 immune-checkpoint inhibition (ICI) therapy in a child with CMMRD-associated glioblastoma.
A 9-year-old boy presented with seizures and a right frontal lobe mass. There was no family history of cancer, consanguinity, or café-au-lait macules. He had been previously treated for colonic adenocarcinoma. This tumor had demonstrated intact MLH1, MSH2, and MSH6 protein expression, with loss of PMS2 staining in both tumor and normal tissue, previously interpreted as a technical error [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e. The brain tumor was resected and confirmed as glioblastoma [Figure 1]f. Immunohistochemistry (IHC) demonstrated a similar pattern, with a complete lack of protein expression of PMS2 in the tumor and normal tissue [Figure 1]g and [Figure 1]h. Correlating the two IHC patterns, this was suggestive of germline, bi-allelic mutations in the PMS2 genes, and compatible with a diagnosis of CMMRD. He was treated with external beam radiation with 59.4 Gy in 33 fractions. Temozolomide was omitted from treatment. Imaging confirmed remission. Whole-body PET scan and colonoscopy revealed no additional tumors. Surveillance was continued.
Germline sequencing in a reference laboratory confirmed double heterozygous mutations in the PMS2 gene (p.Ser815Leu and p.Gln275Gln). Additionally, somatic hit in the DNA-polymerase-ε gene (POLE; p.Leu424Pro) was detected. Mutational signatures 6 and 15 (suggestive of DNA-mismatch repair deficiency), along with signature 10 (suggestive of DNA-polymerase deficiency), were demonstrated [Figure 1]i. These confirmed that the tumor had become completely DNA-replication repair deficient (RRD) due to mutations in both MMR and polymerase pathways. This reflected in an “ultra-hypermutator” phenotype, with a tumor mutation burden (TMB) of 205.92 mutations/megabase. A pathogenic TP53 mutation (p.Tyr126Ter) was detected. The adenocarcinoma had a TMB of 338.32 mutations/megabase and demonstrated MMR mutational signatures [Figure 1]j.
Radiological progression of the glioblastoma within 4 months prompted initiation of ICI with Nivolumab (3 mg/kg/dose) every 2 weeks [Figure 1]k and [Figure 1]l. Following two doses, he presented with new-onset headache, vomiting, and VIIth nerve palsy. “Immune flare” causing pseudo-progression was considered. Treatment with a 7-day course of rapidly tapering dexamethasone resulted in complete symptom resolution. Nivolumab, continued via compassionate access every 3 weeks, was well-tolerated, with demonstration of radiological response [Figure 1]m and [Figure 1]n. Unfortunately, symptomatic progression was diagnosed after 8 months of ICI therapy [Figure 1]o. Parents refused further treatment and the child died 18 months following diagnosis. Family screening revealed heterozygous PMS2 mutation in the sibling. He was offered counseling for Lynch syndrome.
Our case highlights the classical issues related to childhood glioblastoma, cancer predisposition, and management in the context of a resource-constrained setting. Up to 40% of PHGG may be RRD-related, especially in regions with increased consanguinity. Prevalence in India is unknown, though the population is a conglomeration of diverse endogamous groups and a potential hotbed for genetic diseases. Our patient lacked family history and had double heterozygous mutations, highlighting that not all necessarily have consanguinity. Cutaneous manifestations and radiological cues (multiple developmental venous anomalies) were absent. The prior history of colon cancer, along with the correct interpretation of the characteristic IHC findings, which are ~ 90% sensitive and 100% specific, clinched the diagnosis. This led to several important clinical decisions.
Temozolomide, a standard chemotherapeutic agent for HGG, is ineffective due to the lack of an intact MMR pathway. It is incriminated in driving treatment-induced hypermutation in gliomas. Thus, this was omitted. Recent reports suggest that these tumors retain sensitivity to Lomustine, which can be considered as a therapeutic option.
Sequencing with TMB and signature analysis confirmed CMMRD and RRD. As this is expensive and restricted to research laboratories, we collaborated with the International RRD Consortium to complete the genomic analysis following the family's consent. Complete RRD resulted in an ultra-hypermutated (>100 mutations/megabase) tumor.
Most relapsed PHGG progress within 1–2 months despite salvage treatment, and survival is usually 3–6 months post-recurrence. The mean time from relapse to death has been previously reported as 2.6 months in CMMRD. However, recent reports have demonstrated dramatic and durable responses to ICI, likely related to the hypermutation resulting in a high neoantigen load., High TMB helped us secure compassionate access to ICI at relapse. The patient had a durable response lasting 8 months and post-recurrence survival of 11 months following ICI, with good quality of life.
New neurological symptoms with radiological “flare” early into ICI treatment are suggestive of drug-effect and should not prompt interruption of therapy. Management is supportive. The role of steroids is ambiguous due to concerns of immunosuppression and interference with the ICI effect but may be lifesaving in critical situations. Animal models suggest that the impact of efficacy on CNS tumors may be less. We used a short course of steroids with rapid recovery and managed to continue ICI. Unfortunately, the patient progressed, and further treatment was refused. Prediction and treatment modulation for progressive disease following ICI are the focus of current research.
We demonstrate that the diagnosis of CMMRD in PHGG is feasible in the Indian setting by using IHC and impacts patient management. Collaboration with reference laboratories and advocacy groups enabled germline analysis, family screening for asymptomatic heterozygotes (Lynch syndrome), and access to ICI. Early diagnosis by surveillance for those affected with bi-allelic mutations may result in survival advantage. Systematic studies with routine incorporation and correct interpretation of MMR staining in the diagnostic algorithm of PHGG in India will help understand the true prevalence of this increasingly recognized condition and improve outcomes for these children and their families.
Financial support and sponsorship
AD is supported by the St.Baldrick's Foundation International Scholar Award (with generous support from the Team Campbell Foundation; Grant no. 697257)
Conflicts of interest
There are no conflicts of interest.
Informed consent was obtained at Tata Medical Center, and by the International RRD Consortium (approved by the SickKids Institutional Ethics Review Board)