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Purpose <p>High-grade gliomas (HGGs) in children and adolescents/young adults (AYAs) are aggressive tumors with a poor prognosis. A subset is driven by constitutional mismatch repair deficiency (CMMRD), an inherited cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. Despite its clinical relevance, data on MMR deficiency (MMR-D) in Indian populations are scarce.</p> Methods <p>We retrospectively analyzed 100 cases of CNS WHO grade 4 diffuse HGGs (2016–2024) from a tertiary care center in North India. MMR protein expression was assessed by immunohistochemistry (IHC). With selected MMR-D cases further analyzed by Whole-exome sequencing (WES), tumor mutational burden (TMB), mutational signatures, and genome-wide methylation profiling. Immune markers, including PD-L1, CTLA-4, CD8, and p53, were also evaluated.</p> Results <p>Complete loss of at least one MMR protein was observed in 11% (11/100) cases, while another 5% (5/100) of cases showed partial loss PMS2 was the most frequently lost protein (62.5%), followed by MSH2, MLH1, and MSH6. Among MMR-D cases, 56.25% were pediatric and 43.75% were AYA, with median ages of 8 and 26 years, respectively. A significant correlation was found between the presence of giant cells and MMR status. WES revealed ultra-hypermutation (TMB &gt; 100 mutations/Mb) in 4/6 tested cases and polymerase (POLE)-associated signatures in 66%. Concurrent mutations in TP53, NF1, and ATRX were frequently observed. Despite high TMB, PD-L1, CTLA-4, and CD8 expression showed no significant association with MMR status</p> Conclusion <p>Our study identified a 11% prevalence of MMR-D in CNS WHO grade 4 HGGs using IHC, with hypermutation predominantly driven by sequential MMR and polymerase pathway defects. These tumors exhibit unique molecular profiles distinct from adult sporadic gliomas and warrant routine MMR testing in pediatric and AYA patients for accurate diagnosis, genetic counseling, and consideration of immunotherapy.</p>

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Unveiling MMR deficiency in pediatric and AYA high-grade gliomas: insights from multiomic profiling

  • 期刊论文

  • 发表日期：

    2025年10月15日

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  • Supriya Bhardwaj,
  • Jyotsna Singh,
  • Swati Singh,
  • Charli Roy,
  • Hemlata Jangir,
  • Shrinidhi Vasant,
  • Sumanta Das,
  • Shweta Kedia,
  • Ajay Garg,
  • Ashish Suri,
  • Mehar Chand Sharma,
  • Jose Rafael Dimayacyac,
  • Lucie Stengs,
  • Uri Tabori,
  • Anirban Das,
  • Chitra Sarkar,
  • Vaishali Suri

摘要

Purpose

High-grade gliomas (HGGs) in children and adolescents/young adults (AYAs) are aggressive tumors with a poor prognosis. A subset is driven by constitutional mismatch repair deficiency (CMMRD), an inherited cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. Despite its clinical relevance, data on MMR deficiency (MMR-D) in Indian populations are scarce.

Methods

We retrospectively analyzed 100 cases of CNS WHO grade 4 diffuse HGGs (2016–2024) from a tertiary care center in North India. MMR protein expression was assessed by immunohistochemistry (IHC). With selected MMR-D cases further analyzed by Whole-exome sequencing (WES), tumor mutational burden (TMB), mutational signatures, and genome-wide methylation profiling. Immune markers, including PD-L1, CTLA-4, CD8, and p53, were also evaluated.

Results

Complete loss of at least one MMR protein was observed in 11% (11/100) cases, while another 5% (5/100) of cases showed partial loss PMS2 was the most frequently lost protein (62.5%), followed by MSH2, MLH1, and MSH6. Among MMR-D cases, 56.25% were pediatric and 43.75% were AYA, with median ages of 8 and 26 years, respectively. A significant correlation was found between the presence of giant cells and MMR status. WES revealed ultra-hypermutation (TMB > 100 mutations/Mb) in 4/6 tested cases and polymerase (POLE)-associated signatures in 66%. Concurrent mutations in TP53, NF1, and ATRX were frequently observed. Despite high TMB, PD-L1, CTLA-4, and CD8 expression showed no significant association with MMR status

Conclusion

Our study identified a 11% prevalence of MMR-D in CNS WHO grade 4 HGGs using IHC, with hypermutation predominantly driven by sequential MMR and polymerase pathway defects. These tumors exhibit unique molecular profiles distinct from adult sporadic gliomas and warrant routine MMR testing in pediatric and AYA patients for accurate diagnosis, genetic counseling, and consideration of immunotherapy.