THE CLINICAL AND BIOLOGICAL LANDSCAPE OF CNS CANCERS IN CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: AN IRRDC COHORT STUDY - Abstract

Q: What is the study trying to determine about CMMRD and CNS cancers?

The study aims to characterize the clinical spectrum, cancer biology, and how genetics affect patient survival, with attention to outcomes after surveillance and immunotherapy for CNS cancers.

Q: How many patients and cancers were included in the IRRDC cohort study?

The cohort enrolled 201 patients between 2007 and 2022, with 194 patients developing 339 cancers overall.

Sep 21, 2026

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Constitutional mismatch repair deficiency (CMMRD) is an aggressive cancer predisposition syndrome with limited data for guiding care, particularly for central nervous system (CNS) tumors. An international IRRDC consortium study analyzed clinical, genomic, and longitudinal outcomes in 201 enrolled patients (2007-2022). CNS cancers showed enrichment for mutations in POLE/POLD1, TP53, IDH1, and RAS/MAPK, which influenced therapy response. Germline MLH1/MSH2 variants drove earlier onset and poorer survival than PMS2/MSH6, and truncating frameshift variants within the same gene worsened outcomes despite improved overall survival after surveillance and immunotherapy. Results support genotype-focused comprehensive assays for precision surveillance and immunotherapy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages1

Reading Time3 min

AccessFree to download

Background

Methods

Results

Conclusion

Abstracts and pathognomonic mutational signatures. CNS cancers were enriched for mutations in POLE/POLD1, TP53, IDH1, and RAS/MAPK compared to hematopoietic and other cancers. These mutations determined response to therapy. Germline MLH1/MSH2 variants caused earlier cancer and CNS tumor onset than PMS2/MSH6, and inferior survival (survival at 15 years: PMS2: 63%, MSH6: 49%, MLH1: 19%, MSH2: 0%, p<0.0001). Strikingly, frameshift/truncating variants within the same gene caused earlier cancersand inferior outcomes (p<0.0001) . The deleterious impact of MLH1/MSH2 persisted despite overall improvement in survival following surveillance and immunotherapy. CONCLUSION: The extreme cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis focusing on specific genotypes to perform precision approaches toward surveillance and immunotherapy. These data will guide the management of children and emerging adult survivors of CMMRD. ABSTRACT CITATION ID: NOAE064.700 OTHR-30. THE CLINICAL AND BIOLOGICAL LANDSCAPE OF CNS CANCERS IN CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: AN IRRDC COHORT STUDY Ayse Bahar Ercan1, Melyssa Aronson2, Nicholas R Fernandez1, Yuan Chang1, Zhihui Amy Liu3, Logine Negm1, Melissa Edwards1, Vanessa Bianchi1, Anita Villani4, David Malkin4, Cynthia Hawkins5, Eric Bouffet4, Anirban Das4, Uri Tabori4; 1Arthur and Sonia Labatt Brain Tumor Research Centre, Toronto, Canada, 2Zane Cohen Centre for Digestive Diseases, Sinai Health System, Toronto, Canada, 3Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, 4Division of Hematology and Oncology, The Hospital for Sick Children, Toronto, Canada, 5Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is an aggressive cancer predisposition syndrome. As a lack of data contributes to management challenges and inferior outcomes, especially in central nervous system (CNS) cancers, we aimed to determine the clinical spectrum, cancer biology, and impact of genetics on patient survival. METHODS: To determine the cancer spectrum, biology, estimated incidence, and impact of genotype on cancer onset and survival, including following surveillance and immunotherapy, we collected cross-sectional, longitudinal, and genomic data on CMMRD patients and their cancers registered to an international consortium. RESULTS: We report 201 patients enrolled between 2007- 2022 (median follow-up: 7.2 years) . Overall, 194 (97%) patients developed 339 cancers. Cumulative cancer and CNS tumor incidence were 93% and 82% by age 20, respectively. Median time between cancers was 2 years. Although neoplasms developed in 15 organs and included early-onset adult cancers, CNS tumors had the earliest median age of diagnosis (9.7 years), were the most common cancer type (51%), and the main cause of death (p<0.0001) . All cancers exhibited high mutation and microsatellite burden, iv200 NEURO-ONCOLOGY • June 2024

FAQs

What is the study trying to determine about CMMRD and CNS cancers?

The study aims to characterize the clinical spectrum, cancer biology, and how genetics affect patient survival, with attention to outcomes after surveillance and immunotherapy for CNS cancers.

How many patients and cancers were included in the IRRDC cohort study?

The cohort enrolled 201 patients between 2007 and 2022, with 194 patients developing 339 cancers overall.

Which genetic differences were associated with earlier onset and worse survival?

Germline MLH1/MSH2 variants caused earlier cancer and CNS tumor onset and inferior survival compared with PMS2/MSH6, and frameshift/truncating variants within the same gene led to earlier cancers and worse outcomes.

Sep 21, 2026

Uploaded by Violet