By Lynda Williams, medwireNews Reporter
medwireNews: Primary mismatch repair deficiency (MMRD) in gliomas is underdiagnosed among people younger than 40 years old, say investigators who recommend assessment of the biomarker to help facilitate checkpoint inhibitor therapy.
“The current evidence suggests that the uniform implementation of a robust screening protocol for primary MMRD in gliomas in children, adolescents, and young adults presenting with specific molecular alterations and clinical features is likely to drastically alter management and disease outcome for these patients”, write Uri Tabori (The Hospital for Sick Children, Toronto, Ontario, Canada) and co-authors in The Lancet Oncology.
The team collated information from the TOR-Ped and TOR-AYA population-based cohorts of children aged 0–17 years (n=233) and adolescents and young adults aged 18–40 years (n=405), respectively, who were diagnosed with gliomas between 2000 and 2019 in Toronto, as well as two other paediatric registries, the St Jude Children’s Research Hospital (n=219; 2015–2021) and the Children’s Brain Tumor Network (n=525; 1981–2021).
Glioma samples from the 1382 patients were assessed for primary MMRD using the LOw-pass Genomic Instability Characterization whole-genome sequencing technique, with a MMRDness score above 0 considered positive for MMRD.
The prevalence of primary MMRD in high-grade gliomas (grades 3–4) was 3.7% in adults and ranged from 4.9–12.4% among children. Primary MMRD in low-grade gliomas (grades 1–2) was identified in 1.4% of adults but just one (0.8%) child with a BRAF V600E-mutated xanthoastrocytoma, which the researchers say “rapidly transformed to a high-grade glioma.”
Further analysis was performed on 40 primary MMRD gliomas and 1129 MMR proficient (MMRP) gliomas. Among children, just 0.7% of H3-mutated high-grade gliomas had primary MMRD versus 62.5% of eight IDH-mutated gliomas and 34.4% of 61 wild-type IDH and H3 cases, all of which had TP53 pathogenic variants.
Among the adult cohort, there were no cases of primary MMRD in high-grade gliomas with H3 mutations or oligodendrogliomas, and just 2.6% of glioblastomas with pathogenic TERT variants or chromosome 7 and/or 10 alterations. Primary MMRD was identified in 18.8% of the 32 other types of glioblastomas, including 33.3% of five with TP53 pathogenic variants.
“[A]lthough germline MMRD predisposition is considered rare, we discovered that most primary MMRD-driven gliomas are caused by germline variants […] rather than the more commonly reported association with [constitutional] MMRD”, Tabori et al say.
Specifically, among 35 cases of primary MMRD gliomas in the children and adults assessed, 33 (94.3%) were associated with a germline mutation and two with a somatic mutation.
Of the germline mutations, 60.6% were associated with Lynch syndrome and 39.4% with constitutional MMRD. The researchers note that there was a significant difference in the distribution of the MMR-associated genes between the two syndromes, with 80.3% of Lynch syndrome cases attributed to pathogenic alterations of MLH1 or MSH2, while 67.9% of constitutional MMRD cases were associated with PMS2 variants. Children with Lynch syndrome were also diagnosed significantly later than those with constitutional MMRD, at a median of 16 versus 10 years, and the researchers believe that patients with underlying cancer predisposition from either syndrome “could benefit from appropriate cancer surveillance strategies and cascade testing of other members in the family.”
Of concern, patients with primary MMRD had “poor” survival, the team reports. Both tumour location (hemispheric vs non-hemispheric) and IDH (mutated vs wild-type) status were significant predictors of overall survival (OS) among the Toronto cohorts, with hazard ratios (HRs) for death of 1.86 and 2.11, respectively.
Primary MMRD status did not significantly affect OS among patients with high-grade gliomas with wild-type IDH. But for IDH-mutated high-grade gliomas treated by chemoradiotherapy, the HR for death was a significant 12.6 for primary MMRD versus MMRP cases.
Furthermore, paediatric patients with primary MMRD gliomas had significantly better 5-year survival when treated with immune checkpoint inhibitors rather than conventional chemotherapy (HR=0.4) and this was true regardless of age or germline status, the investigators emphasise.
Tabori et al conclude that the significant immunotherapy benefit “across age and syndromes” in the study “could facilitate drug access” in children with glioma and MMRD.
“These data, therefore, have important implications not only for individual patients, but also for their extended families, treating physicians, and policy advocates”, they say.
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Lancet Oncol 2024; doi:10.1016/S1470-2045