Constitutional mismatch repair deficiency is a childhood cancer predisposition syndrome associated with an increased risk of high grade paediatric brain tumours: report of 3 cases and review of the literature

Abstract BACKGROUND Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition syndrome caused by biallelic mutations in the mismatch repair pathway, and high-grade glioma (HGG) constitute the most prevalent brain tumours. Pseudoprogression alludes to radiological changes that mimic tumour progression, but are in fact due to other causes such as therapy related inflammation. It can occur as early as three months post treatment. To our knowledge, its characteristics in CMMRD patients has not been reported. METHODS We retrospectively identified seven patients with CMMRD and history of HGG at The Royal Children’s Hospital, Melbourne from 2005 to 2019. Our objective was to review the characteristics of pseudoprogression in this cohort. RESULTS Out of the seven patients, two with constitutional loss of PMS2 demonstrated evidence of pseudoprogression. Patient 1 presented at 16 years old with a cerebellar anaplastic astrocytoma. She developed clinical and radiological progression within two weeks of starting radiotherapy, persisting up to four months after completion. However, six months post radiation she improved without intervention and the tumour remains stable five years post therapy. Patient 2 presented at 17 years old with a midbrain anaplastic astrocytoma, and showed signs of progression four weeks after completion of radiotherapy. She was then treated with Bevacizumab, an anti-VEGFA antibody with remarkable response. She subsequently received Nivolumab, a checkpoint inhibitor with ongoing stable disease for four months. CONCLUSION Our findings showed that pseudoprogression can occur early in the treatment course in CMMRD patients. Identification of this entity is important for appropriate clinical management.

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Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome

Cancers ◽

10.3390/cancers13102345 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2345

Author(s):

Asima Abidi ◽

Mark A. J. Gorris ◽

Evan Brennan ◽

Marjolijn C. J. Jongmans ◽

Dilys D. Weijers ◽

...

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Immune Checkpoint ◽

Immune Escape ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Increased Risk ◽

Hla Binding ◽

Risk Of Cancer ◽

Constitutional Mismatch Repair Deficiency

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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Constitutional mismatch repair deficiency–associated brain tumors: report from the European C4CMMRD consortium

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz033 ◽

2019 ◽

Vol 1 (1) ◽

Cited By ~ 1

Author(s):

Léa Guerrini-Rousseau ◽

Pascale Varlet ◽

Chrystelle Colas ◽

Felipe Andreiuolo ◽

Franck Bourdeaut ◽

...

Keyword(s):

Brain Tumors ◽

Mismatch Repair ◽

Giant Cells ◽

Mismatch Repair Deficiency ◽

Cancer Predisposition Syndrome ◽

Multinucleated Cells ◽

Brain Anomalies ◽

Repair Deficiency ◽

Constitutional Mismatch Repair Deficiency

Abstract Background Malignant brain tumors (BT) are among the cancers most frequently associated with constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations in mismatch repair genes. This study analyzed data from the European “Care for CMMRD” (C4CMMRD) database to describe their clinical characteristics, treatments, and outcome with the aim of improving its diagnosis/treatment. Methods Retrospective analysis of data on patients with CMMRD and malignant BT from the C4CMMRD database up to July 2017. Results Among the 87 registered patients, 49 developed 56 malignant BTs: 50 high-grade gliomas (HGG) (with giant multinucleated cells in 16/21 histologically reviewed tumors) and 6 embryonal tumors. The median age at first BT was 9.2 years [1.1–40.6], with nine patients older than 18. Twenty-seven patients developed multiple malignancies (including16 before the BT). Most patients received standard treatment, and eight patients immunotherapy for relapsed HGG. The 3- and 5-year overall survival (OS) rates were 30% (95% CI: 19–45) and 22% (95% CI: 12–37) after the first BT, with worse prognosis for HGG (3-year OS = 20.5%). Six patients were alive (median follow-up 2.5 years) and 43 dead (38 deaths, 88%, were BT-related). Other CMMRD-specific features were café-au-lait macules (40/41), multiple BTs (5/15), developmental brain anomalies (11/15), and consanguinity (20/38 families). Conclusions Several characteristics could help suspecting CMMRD in pediatric malignant BTs: giant cells on histology, previous malignancies, parental consanguinity, café-au-lait macules, multiple BTs, and developmental brain anomalies. The prognosis of CMMRD-associated BT treated with standard therapies is poor requiring new therapeutic up-front approaches.

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RARE-23. NOVEL NF1 MUTATIONS IN TWO OCCURRENCES OF GLIOBLASTOMA MULTIFORM IN A PATIENT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME

Neuro-Oncology ◽

10.1093/neuonc/noaa222.734 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii447-iii447

Author(s):

Kaylyn Utley ◽

Jens Reuter ◽

Lei Li ◽

Devon Evans ◽

Jeffrey Florman ◽

...

Keyword(s):

Colon Cancer ◽

Mismatch Repair ◽

Stage Iv ◽

Deficiency Syndrome ◽

Genetic Profile ◽

Molecular Testing ◽

Mismatch Repair Deficiency ◽

Cancer Predisposition Syndrome ◽

Repair Deficiency ◽

Constitutional Mismatch Repair Deficiency

Abstract Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare cancer predisposition syndrome in children. Its main associated tumor types include brain and CNS tumors, hematologic malignancies, intestinal polyps and colorectal tumors, and other malignancies. Tumor genesis within this population is highly complex and poorly understood. We describe a case of a patient with two occurrences of glioblastoma multiforme (GBM), each with unique NF1 mutations. The patient is a female with CMMRD who was first diagnosed with GBM of the right frontal lobe in 2015. She subsequently underwent gross total resection, radiation to the field and concomitant and maintenance therapy with Temozolomide and Everolimus, due to high suspicion for NF-1. Genetic studies didn’t show NF-1, instead revealing a diagnosis of CMMRD. Molecular testing of the GBM showed a high mutational burden and an NF1 mutation. Later, screening revealed stage IV colon cancer, for which she underwent subtotal colectomy, partial liver resection and chemotherapy. Molecular testing from the colon cancer found a hypermutant malignancy without mutations in NF1. Surveillance imaging detected a mass at the original site of her GBM, for which she had a resection. Notably, the genetic profile of the second tumor substantially different from the original tumor and the colon cancer sample, but had new mutations in NF-1. These findings highlight the significant variability in the genetic profiles of tumors in the context of CMMRD. It is also worth considering that NF1 is one of the first in a cascade of mutations leading to GBM in these patients.

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Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107627 ◽

2021 ◽

pp. jmedgenet-2020-107627

Author(s):

Melyssa Aronson ◽

Chrystelle Colas ◽

Andrew Shuen ◽

Heather Hampel ◽

William D Foulkes ◽

...

Keyword(s):

Literature Review ◽

Mismatch Repair ◽

Diagnostic Criteria ◽

Working Group ◽

Extensive Literature ◽

Mismatch Repair Deficiency ◽

International Consensus ◽

Cancer Predisposition Syndrome ◽

Repair Deficiency ◽

Constitutional Mismatch Repair Deficiency

BackgroundConstitutional mismatch repair deficiency syndrome (CMMRD) is the most aggressive cancer predisposition syndrome associated with multiorgan cancers, often presenting in childhood. There is variability in age and presentation of cancers and benign manifestations mimicking neurofibromatosis type 1. Genetic testing may not be informative and is complicated by pseudogenes associated with the most commonly associated gene, PMS2. To date, no diagnostic criteria exist. Since surveillance and immune-based therapies are available, establishing a CMMRD diagnosis is key to improve survival.MethodsIn order to establish a robust diagnostic path, a multidisciplinary international working group, with representation from the two largest consortia (International Replication Repair Deficiency (IRRD) consortium and European Consortium Care for CMMRD (C4CMMRD)), was formed to establish diagnostic criteria based on expertise, literature review and consensus.ResultsThe working group established seven diagnostic criteria for the diagnosis of CMMRD, including four definitive criteria (strong evidence) and three likely diagnostic criteria (moderate evidence). All criteria warrant CMMRD surveillance. The criteria incorporate germline mismatch repair results, ancillary tests and clinical manifestation to determine a diagnosis. Hallmark cancers for CMMRD were defined by the working group after extensive literature review and consultation with the IRRD and C4CMMRD consortia.ConclusionsThis position paper summarises the evidence and rationale to provide specific guidelines for CMMRD diagnosis, which necessitates appropriate surveillance and treatment.

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Constitutional mismatch repair deficiency (CMMRD) presenting with high-grade glioma, multiple developmental venous anomalies and malformations of cortical development—a multidisciplinary/multicentre approach and neuroimaging clues to clinching the diagnosis

Child s Nervous System ◽

10.1007/s00381-020-04986-9 ◽

2020 ◽

Author(s):

Sahil Chhabda ◽

Sniya Sudhakar ◽

Kshitij Mankad ◽

Mette Jorgensen ◽

Fernando Carceller ◽

...

Keyword(s):

Mismatch Repair ◽

Cortical Development ◽

High Grade Glioma ◽

High Grade ◽

Malformations Of Cortical Development ◽

Mismatch Repair Deficiency ◽

Venous Anomalies ◽

Repair Deficiency ◽

Developmental Venous Anomalies ◽

Constitutional Mismatch Repair Deficiency

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Presentation of Acute Lymphoblastic Lymphoma and Colorectal Carcinoma in the Context of Constitutional Mismatch Repair Deficiency Syndrome (CMMRD): a Case Report with Literature Review

Journal of Cancer & Allied Specialties ◽

10.37029/jcas.v8i1.443 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Muhammad Irfan Basheer ◽

Iftikhar Ali Rana ◽

Umer Nisar Sheikh ◽

Muhammed Aasim Yusuf ◽

Irfana Ishaq Sindhu ◽

...

Keyword(s):

Mismatch Repair ◽

Tumor Cells ◽

Cervical Lymphadenopathy ◽

Lymphoblastic Lymphoma ◽

Pediatric Tumors ◽

Mismatch Repair Deficiency ◽

Repair Deficiency ◽

Increased Risk ◽

History Of ◽

Constitutional Mismatch Repair Deficiency

Introduction: Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive disease-carrying an increased risk of cancers (pediatric tumors of central nervous system, haemato-lymphoid malignancies along with gastrointestinal (GI) cancer(s), which are usually seen in the second and third decade) leading to syndromic presentation. Causal mutations are detected in DNA mismatch repair (MMR) genes, including MLH1, PMS2, MSH2, and MSH6 that are also known for their established role in Lynch syndrome. We describe a case of CMMRD with an earlier (first decade of life) presentation of mediastinal acute lymphoblastic lymphoma and colorectal malignancy. Case Presentation: A five-year-old boy presented with respiratory complaints, bilateral cervical lymphadenopathy, multiple café au lait macules (CALMs) on the lower back, history of parental consanguinity with the death of three sisters due to brain tumor within 6 months of diagnosis. Computerized tomographic (CT) scan chest revealed a huge mediastinal mass. The patient underwent a trucut-biopsy of the mass. The results were significant for a pre T-cell acute lymphoblastic lymphoma. Suspicion of CMMRD was raised based on a combination of factors described above. A panel of mismatch repair (MMR) proteins was applied on the biopsy tissue that revealed loss of nuclear expression of MLH1 and PMS2 immunostaining in tumor cells with positive external controls. While on maintenance therapy for lymphoma, about a year later, the patient developed sub-acute intestinal obstruction due to a stenosing polypoidal circumferential tumor in the mid-sigmoid colon found on flexible sigmoidoscopy that was followed by endoscopic biopsies and insertion of a fully-covered self-expanding metallic adult biliary stent with a diameter of 10 mm and length of 6 cm leading to immediate relief of obstruction. Biopsies revealed adenocarcinoma with neuroendocrine differentiation. Metastatic tumor deposits were seen in the omentum, anterior abdominal wall, and the left peritoneal wall. Practical Implications: Earlier (first decade) presentation of gastrointestinal malignancy warrants that an earlier screening through radiological scans for any possible tumors and MMR protein expression analysis (loss in tumor plus normal non-tumor cells) are essential in patients having CALMs and family history of pediatric tumors.

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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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