Background: Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0-40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults.
Methods: Clinical and molecular data were collected from a population-based cohort of children, adolescents, and young adults with gliomas from Toronto (TOR-Ped, age 0-18 years, collected Jan 1, 2000, to Dec 31, 2021; and TOR-AYA, age 18-40 years, collected Jan 1, 2000, to June 30, 2019). Additional validation paediatric cohorts from St Jude Children's Research Hospital (0-18 years, 2015-21) and the Children's Brain Tumor Network (0-18 years, 1981-2021) were used. Functional genomic tools were applied with the primary aim of assessing primary MMRD prevalence among glioma subgroups and germline impact. To evaluate the effect of primary MMRD on therapy and overall survival, Kaplan-Meier estimates were used on an additional cohort of patients with primary MMRD gliomas treated with immunotherapy.
Findings: 1389 gliomas were included in the study. The prevalence of primary MMRD ranged between 3·7% and 12·4% in high-grade gliomas (overall 30 of 483; 6·2%, 95% CI 4·2-8·7) and less than 1% in low-grade gliomas (four of 899; 0·4%, 0·1-1·1; p<0·0001 by χ test). Specific molecular analysis for all gliomas showed that primary MMRD was absent among oligodendrogliomas (none of 67) and uncommon in BRAF gliomas (one of 110) and histone mutant-driven gliomas (one of 150). In the paediatric age group (<18 years), primary MMRD was common in IDH and H3 gliomas harbouring pathogenic TP53 variants (21 of 61; 34·4%, 22·7-47·7) and in malignant IDH gliomas (five of eight; 62·5%, 24·5-91·5). Germline aetiology accounted for 33 (94·3%) of 35 primary MMRD gliomas, including children, adolescents, and young adults with previously unrecognised Lynch syndrome. Survival was poor for patients with primary MMRD gliomas. Particularly poor survival was observed for those with IDH astrocytomas with primary MMRD when compared with those with mismatch repair-proficient gliomas (HR 12·6, 95% CI 2·8-57·5; p=0·0011 by multivariable Cox regression). Immune checkpoint blockade was associated with improved survival for patients with primary MMRD gliomas compared with conventional chemoradiotherapy regimens (HR 0·4, 0·3-0·7; p=0·0017 by multivariable Cox regression), regardless of age or germline status.
Interpretation: 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.
Funding: The Canadian Institutes for Health Research, Stand Up to Cancer-Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Canada's Immunotherapy Network, Harry and Agnieszka Hall, Meagan's Hug, BRAINchild Canada, and the LivWise Foundation.
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http://dx.doi.org/10.1016/S1470-2045(24)00640-5 | DOI Listing |
Lancet Oncol
December 2024
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada. Electronic address:
Background: Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0-40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults.
View Article and Find Full Text PDFAm J Cancer Res
November 2024
Department of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University Xi'an 710032, Shaanxi, China.
Microsatellite instability-high (MSI-H) is a critical biomarker for immunotherapy, yet primary resistance remains a significant challenge. Current MSI-H detection methods evaluate the proportion of MSI-H loci, termed molecular MSI-H score, which can be affected by intratumoral heterogeneity (ITH). To address this limitation, we propose evaluating MSI-H at the cellular level to improve the prediction of immunotherapy outcomes.
View Article and Find Full Text PDFJ Gynecol Oncol
October 2024
Department of Obstetrics and Gynecology, Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Eur J Obstet Gynecol Reprod Biol
November 2024
Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Obstetric and Gynecologic Diseases, Beijing, People's Republic of China. Electronic address:
Introduction: This systematic review and meta-analysis aimed to describe the oncological and reproductive outcomes of patients with MSI-H/MMRd endometrial carcinoma (EC) or atypical endometrial hyperplasia (AEH) undergoing fertility-sparing treatment.
Methods: The study protocol was registered with the PROSPERO database (No: CRD42024530406). A systematic literature search in major electronic databases (PubMed, Embase, and Cochrane Library) was conducted from January 1, 2013 to August 10, 2024.
Am J Surg Pathol
September 2024
Department of Pathology.
In this study, molecular alterations in endometrial carcinoma (EC) recurrences were analyzed. We aimed to identify genes implicated in tumor progression and to evaluate whether histologic and molecular type shifting occurs in recurrences. Thus, we analyzed 50 samples corresponding to 24 primary ECs (15 low-grade endometrioid endometrial carcinomas [LG-EECs] and 9 high-grade endometrial carcinomas) and their corresponding 26 recurrences.
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