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

2019 ◽  
Vol 1 (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.

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

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.

scholarly journals EPID-09. CMMRD (CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY) ASSOCIATED-BRAIN TUMORS: REPORT FROM THE EUROPEAN C4CMMRD CONSORTIUM

2018 ◽  
Vol 20 (suppl_2) ◽  
pp. i82-i82 ◽  
Author(s):  
Léa Guerrini-Rousseau ◽  
Chrystelle Colas ◽  
Katharina Wimmer ◽  
Christine Devalck ◽  
Enrico Opocher ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Mismatch Repair ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Constitutional Mismatch Repair Deficiency

scholarly journals RARE-15. EARLY PSEUDOPROGRESSION POST-RADIATION IN PAEDIATRIC HIGH-GRADE GLIOMA PATIENTS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: TWO CASE REPORTS FROM A SINGLE CENTRE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii444-iii445
Author(s):  
Ay-Jiuan Teng ◽  
Breege Gilmartin ◽  
Marty Campbell ◽  
Kanika Bhatia ◽  
Greg Wheeler ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Anaplastic Astrocytoma ◽  
Tumour Progression ◽  
High Grade Glioma ◽  
High Grade ◽  
Mismatch Repair Deficiency ◽  
Cancer Predisposition Syndrome ◽  
Repair Deficiency ◽  
Post Radiation ◽  
Constitutional Mismatch Repair Deficiency

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.

scholarly journals RARE-17. SURVIVAL BENEFIT FOR INDIVIDUALS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME AND BRAIN TUMORS WHO UNDERGO SURVEILLANCE PROTOCOL. A REPORT FROM THE INTERNATIONAL REPLICATION REPAIR CONSORTIUM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii445-iii446
Author(s):  
Ayse Bahar Ercan ◽  
Carol Durno ◽  
Vanessa J Bianchi ◽  
Melissa Edwards ◽  
Melyssa Aronson ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Mismatch Repair ◽  
Survival Benefit ◽  
Deficiency Syndrome ◽  
Low Grade ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency ◽  
Surveillance Protocol ◽  
Total Body ◽  
Constitutional Mismatch Repair Deficiency

Abstract BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p<0.004). Similarly, 5-year survival was 82+/-11% and 24+/-6% for surveillance and non-surveillance of brain tumors (p=0.005). Yearly total body and q6 month brain MRI detected asymptomatic cancers in all but 3 symptomatic CNS gliomas. These were tumors uncovered when time between scans was >6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors.

scholarly journals IMMU-14. IMMUNE CHECKPOINT INHIBITOR THERAPY FOR TREATMENT OF SYNCHRONOUS CANCERS IN PAEDIATRIC PATIENTS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii362-iii362
Author(s):  
Jacob Henderson ◽  
Daniel Morgenstern ◽  
Melissa Edwards ◽  
Sumedha Sudhaman ◽  
David Kram ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Definitive Treatment ◽  
Mismatch Repair Deficiency ◽  
Synchronous Tumors ◽  
Repair Deficiency ◽  
Initial Tumor ◽  
Synchronous Cancers ◽  
Constitutional Mismatch Repair Deficiency

Abstract Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive condition in which affected patients carry biallelic germline mutations in the MMR genes. This highly penetrant syndrome results in nearly universal development of malignant neoplasms at a young age, most commonly pediatric brain tumors. Importantly, in addition to brain tumors, patients frequently develop multiple metachronous or even synchronous tumors making it impossible to treat these cancers with current chemotherapeutic approaches due to the complexity of different chemoradiation regimens required, resulting in excess toxicity and lack of efficacy. We first, assessed the metachronous (defined here as serial tumors diagnosed >1 year apart or after completion of definitive treatment for the initial tumor) or synchronous cancers (defined here as tumors diagnosed within a year of each other or during the definitive treatment for the initial tumor) in all patients within the consortium. Strikingly, 47% developed synchronous and/or metachronous cancers leading to patient demise. Molecular analysis revealed that all synchronous tumors (n=26) harbored a hypermutational burden accompanied by high genomic microsatellite instability and the relevant signatures. We therefore treated two patients with glioblastomas who had synchronous solid tumors with checkpoint inhibitors. In both patients, objective tumor response was associated with clinical benefit and prolonged survival. Biomarker analysis revealed increased tumor mutational burden, microsatellite instability and immune cell infiltration. These cases highlight the role of universal, mechanism based and tumor-agnostic approach to treat patients with brain tumors with additional synchronous cancers in the setting of cancer predisposition.

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

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.

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

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.

scholarly journals 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

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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