Constitutional mismatch repair deficiency–associated brain tumors: report from the European C4CMMRD consortium

Abstract

Background Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European “Care for CMMRD” (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1–40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19–45) and 22% (95% CI: 12–37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis

“…There is no difference between overall survival of PMMRDIA patients compared to CMMRD patients with IDH-wildtype high-grade gliomas published by the European C4CMMRD consortium (Supplementary Fig. 2, online resource, [ 24 ]). All except one of the 19 patients with PMMRDIA died within 26 months, including the single patient of the cohort with a WHO grade II tumor which had an OS of only 12 months.…”

“…For case 17 survival was calculated starting from diagnosis of the recurrent tumor as this was the only material available for analyses. For the Kaplan–Meier curve comparing the overall survival of patients with PMMRDIA and IDH-wt high-grade gliomas in CMMRD data from Guerrini-Rousseau et al, 2019 [ 24 ] were extracted. Data from patients with anaplastic astrocytoma or glioblastoma were included, excluding IDH-mutant tumors.…”

“…Recently, the European C4CMMRD consortium reported about brain tumors occurring in patients with CMMRD. Notably, the vast majority of these tumors were high-grade gliomas but from 26 tumors available for histological review, only one was identified as IDH-mutant [ 24 ]. A recent case report described the concomitant occurrence of an IDH wildtype and an IDH-mutant glioma in a patient with CMMRD [ 22 ].…”

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

“…2c,d and Extended Data Fig. 1c) 7,9,12,44 . All patients with non-CNS solid tumours continuing ICI had durable responses and are alive at a median follow-up of 2.6 years (range: 0.38-3.5).…”

Radiation-Associated Glioblastoma after Prophylactic Cranial Irradiation in a Patient of ALL: Review of Literature and Report of a Rare Case

“…The illustrative patient did not have any stigmata of neurofibromatosis type 1. Majority of the patients with HGG associated with constitutional mismatch repair-deficiency syndrome have developmental brain vascular anomalies on radiology and giant multinucleated cells on histology, and these particular findings were also absent in this case [30]. However, in hindsight, genetic testing for p53 and mismatch repair genes would have been worthwhile in this illustrative patient.…”