Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome

Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary disorders characterised by a highly increased risk of cancer development. This is due to germline aberrations in the mismatch repair (MMR) genes, which results in a high mutational load in tumours of these patients, including insertions and deletions in genes bearing microsatellites. This generates microsatellite instability and cause reading frameshifts in coding regions that could lead to the generation of neoantigens and opens up avenues for neoantigen targeting immune therapies prophylactically and therapeutically. However, major obstacles need to be overcome, such as the heterogeneity in tumour formation within and between LS and CMMRD patients, which results in considerable variability in the genes targeted by mutations, hence challenging the choice of suitable neoantigens. The machine-learning methods such as NetMHC and MHCflurry that predict neoantigen- human leukocyte antigen (HLA) binding affinity provide little information on other aspects of neoantigen presentation. Immune escape mechanisms that allow MMR-deficient cells to evade surveillance combined with the resistance to immune checkpoint therapy make the neoantigen targeting regimen challenging. Studies to delineate shared neoantigen profiles across patient cohorts, precise HLA binding algorithms, additional therapies to counter immune evasion and evaluation of biomarkers that predict the response of these patients to immune checkpoint therapy are warranted.

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Lynch syndrome–associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome

Molecular Case Studies ◽

10.1101/mcs.a003863 ◽

2019 ◽

Vol 5 (5) ◽

pp. a003863 ◽

Cited By ~ 1

Author(s):

Chen Yang ◽

Frances Austin ◽

Hope Richard ◽

Michael Idowu ◽

Vernell Williamson ◽

...

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Deficiency Syndrome ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Pediatric Glioblastoma ◽

Constitutional Mismatch Repair Deficiency

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Faculty Opinions recommendation of Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718206849.793492961 ◽

2014 ◽

Author(s):

Randall Brand

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Somatic Mutations ◽

Mismatch Repair Deficiency ◽

Repair Deficiency

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RARE-55. CHALLENGES AND SPECIFIC STRATEGIES FOR CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME IN LOW RESOURCE SETTINGS. ON BEHALF OF THE INTERNATIONAL RRD CONSORTIUM IN LOW RESOURCE SETTINGS PANEL

Neuro-Oncology ◽

10.1093/neuonc/noaa222.765 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii454-iii454

Author(s):

Rejin Kebudi ◽

Nisreen Amayiri N ◽

Malak Abedalthagafi ◽

Asim Noor Rana ◽

Slman Kirmani ◽

...

Keyword(s):

Mismatch Repair ◽

Checkpoint Inhibitors ◽

Immune Therapy ◽

Malignant Gliomas ◽

Mismatch Repair Deficiency ◽

Term Survival ◽

Low Resource Settings ◽

Low Resource ◽

Repair Deficiency ◽

Constitutional Mismatch Repair Deficiency

Abstract Germline biallelic mutations in one of the mismatch repair genes (MSH2/MSH6/MLH1/PMS2 results in constitutional mismatch repair deficiency (CMMRD), a condition associated with multiple tumors arising from multiple organs during childhood, and these individuals rarely reach adulthood. The paucity of information with respect to these conditions leads to mismanagement and may be a factor in the high mortality of patients with CMMRD. Two international consortia, the European CARE4CMMRD, and the international replication repair deficiency (RRD) consortium, are addressing the many challenges associated with this condition. To address specific issues surrounding the management of CMMRD in low and middle income countries (LMIC), a multidisciplinary taskforce of 11 specialists from nine countries was formed. Preliminary conclusions are: 1) Immunohistochemistry for CMMRD should be considered for all patients with suggestive clinical features. In countries where CMMRD is common, malignant gliomas, colon cancers and T cell lymphomas should be stained routinely as the prevalence of CMMRD in these tumors can exceed 40%. 2) Temozolomide should not be used in the management of malignant glioma. By contrast, preclinical studies have suggested increased sensitivity to nitrosoureas. For the management of CMMRD related lymphoma and leukemia, mercaptopurines should not be avoided or discontinued as a part of the standard of care before more data are collected. 3) Management with checkpoint inhibitors should be limited to centers with intensive care units and expertise in complex supportive care to manage side effects of immune therapy. 4) Surveillance protocols have demonstrated long term survival benefits and should be implemented in LMIC.

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The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals

International Journal of Molecular Sciences ◽

10.3390/ijms22094629 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4629

Author(s):

Cristina Carrato ◽

Carolina Sanz ◽

Ana María Muñoz-Mármol ◽

Ignacio Blanco ◽

Marta Pineda ◽

...

Keyword(s):

Brain Tumors ◽

Mismatch Repair ◽

Rare Event ◽

Deficiency Syndrome ◽

Mismatch Repair Deficiency ◽

Malignant Brain Tumors ◽

Repair Deficiency ◽

Clinical Awareness ◽

High Degree ◽

Constitutional Mismatch Repair Deficiency

Biallelic germline mismatch repair (MMR) gene (MLH1, MSH2, MSH6, and PMS2) mutations are an extremely rare event that causes constitutional mismatch repair deficiency (CMMRD) syndrome. CMMRD is underdiagnosed and often debuts with pediatric malignant brain tumors. A high degree of clinical awareness of the CMMRD phenotype is needed to identify new cases. Immunohistochemical (IHC) assessment of MMR protein expression and analysis of microsatellite instability (MSI) are the first tools with which to initiate the study of this syndrome in solid malignancies. MMR IHC shows a hallmark pattern with absence of staining in both neoplastic and non-neoplastic cells for the biallelic mutated gene. However, MSI often fails in brain malignancies. The aim of this report is to draw attention to the peculiar IHC profile that characterizes CMMRD syndrome and to review the difficulties in reaching an accurate diagnosis by describing the case of two siblings with biallelic MSH6 germline mutations and brain tumors. Given the difficulties involved in early diagnosis of CMMRD we propose the use of the IHC of MMR proteins in all malignant brain tumors diagnosed in individuals younger than 25 years-old to facilitate the diagnosis of CMMRD and to select those neoplasms that will benefit from immunotherapy treatment.

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