In a cohort study reported in The Lancet Oncology, Negm et al found that primary mismatch repair deficiency (MMRD) was associated with poor outcomes in children, adolescents, and young adults with gliomas.
Study Details
In the study, clinical and molecular data were collected from children, adolescents, and young adults with gliomas from a Toronto cohort of pediatric patients (age = 0–18 years, collected between January 2000 and December 2021) and a Toronto cohort of adolescents and young adults (age 18–40 years, collected between January 2000 and June 2019).
Key Findings
A total of 1,389 gliomas were included in the study. The prevalence of primary MMRD ranged from 3.7% to 12.4% in high-grade gliomas (overall = 30/483, 6.2%, 95% confidence interval [CI] = 4.2%–8.7%) and was significantly greater than (P < .0001) the < 1% prevalence in low-grade gliomas (4/899, 0.4%, 95% CI = 0.1%–1.1%).
Molecular analysis showed that primary MMRD was absent among oligodendrogliomas (0 of 67) and uncommon in BRAF V600E–mutant gliomas (1 of 110) and histone mutant–driven gliomas (1 of 150). In the pediatric age group, primary MMRD was common in IDH wild-type and H3 wild-type gliomas with pathogenic TP53 variants (21/61, 34.4%, 95% CI = 22.7%–47.7%) and in malignant IDH-mutant gliomas (5/8, 62.5%, 95% CI = 24.5%–91.5%).
Germline etiology accounted for 33 (94.3%) of 35 primary MMRD gliomas, including in children, adolescents, and young adults with previously unrecognized Lynch syndrome.
Patients with primary MMRD gliomas had poorer overall survival; in particular, poor survival was observed among patients with IDH-mutant astrocytomas with primary MMRD vs those with mismatch repair–proficient gliomas (hazard ratio [HR] = 12.6, 95% CI = 2.8–57.5, P = .0011). Immune checkpoint inhibitor treatment was associated with improved survival vs conventional chemotherapy among patients with primary MMRD gliomas (HR = 0.4, 95% CI = 0.3–0.7, P = .0017) irrespective of age or germline status.
The investigators concluded: “Primary MMRD is more common than previously reported in gliomas in children, adolescents, and young adults; is enriched in specific molecular subgroups; and is associated with poor outcomes. Accurate detection, genetic testing, early diagnosis through surveillance, and implementation of immunotherapy might improve survival for these patients.”
Uri Tabori, MD, of Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Canadian Institutes for Health Research, Stand Up to Cancer—Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, and others. For full disclosures of the study authors, visit thelancet.com.
