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1
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Mar K, Ameri K, Lam JM. Constitutional Mismatch Repair Deficiency: Scoping Review of a Cancer-Predisposition Syndrome With Distinctive Cutaneous Findings. Pediatr Dermatol 2025; 42:437-446. [PMID: 39910726 PMCID: PMC12118531 DOI: 10.1111/pde.15878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/05/2025] [Accepted: 01/11/2025] [Indexed: 02/07/2025]
Abstract
Constitutional mismatch repair deficiency (CMMRD) is a rare but severe hereditary cancer predisposition syndrome caused by biallelic pathogenic variants in one of the mismatch repair genes (MLH1, MSH2, MSH6, or PMS2). The condition mainly presents in childhood, with cancers primarily affecting the hematological, brain, and gastrointestinal systems, along with cutaneous features typical of neurofibromatosis type 1. This scoping review aims to explore the clinical characteristics of CMMRD. A systematic search of medical databases resulted in the inclusion of 127 articles. PMS2 is the most affected gene, followed by MSH6, MLH1, and MSH2. Blood and brain malignancies occur in early childhood for all genetic variants, with the age of onset progressively decreasing from PMS2 to MSH6, to MLH1 and MSH2. Gastrointestinal tumors typically present in late adolescence in individuals with PMS2 variants, at slightly younger ages in those with MSH6 variants, and are rarely reported in MLH1 and MSH2 cases. Patients with CMMRD present with café-au-lait macules that are fewer in number and larger than in patients with neurofibromatosis type 1. Additional dermatological findings include hypopigmented patches and intertriginous freckling. PMS2 and MSH6 pathogenic variants are linked to the broadest spectrum of cutaneous manifestations, including vascular tumors, various nevi, and pilomatricomas. Despite its rarity and diverse clinical manifestations, advancements in diagnostic criteria, genetic testing, and surveillance protocols have significantly improved survival rates and cancer management in CMMRD patients.
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Affiliation(s)
- Kristie Mar
- Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Kimia Ameri
- Faculty of MedicineUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Joseph M. Lam
- Department of PaediatricsUniversity of British ColumbiaVancouverBritish ColumbiaCanada
- Department of Dermatology and Skin ScienceUniversity of British ColumbiaVancouverBritish ColumbiaCanada
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2
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Aleid AM, Alrasheed AS, Aldanyowi SN, Almalki SF. Advanced magnetic resonance imaging for glioblastoma: Oncology-radiology integration. Surg Neurol Int 2024; 15:309. [PMID: 39246787 PMCID: PMC11380898 DOI: 10.25259/sni_498_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2024] [Accepted: 08/09/2024] [Indexed: 09/10/2024] Open
Abstract
Background Aggressive brain tumors like glioblastoma multiforme (GBM) pose a poor prognosis. While magnetic resonance imaging (MRI) is crucial for GBM management, distinguishing it from other lesions using conventional methods can be difficult. This study explores advanced MRI techniques better to understand GBM properties and their link to patient outcomes. Methods We studied MRI scans of 157 GBM surgery patients from January 2020 to March 2024 to extract radiomic features and analyze the impact of fluid-attenuated inversion recovery (FLAIR) resection on survival using statistical methods, proportional hazards regression, and Kaplan-Meier survival analysis. Results Predictive models achieved high accuracy (area under the curve of 0.902) for glioma-grade prediction. FLAIR abnormality resection significantly improved survival, while diffusion-weighted image best-depicted tumor infiltration. Glioblastoma infiltration was best seen with advanced MRI compared to metastasis. Glioblastomas showed distinct features, including irregular shape, margins, and enhancement compared to metastases, which were oval or round, with clear edges and even contrast, and extensive peritumoral changes. Conclusion Advanced radiomic and machine learning analysis of MRI can provide noninvasive glioma grading and characterization of tumor properties with clinical relevance. Combining advanced neuroimaging with histopathology may better integrate oncology and radiology for optimized glioblastoma management. However, further studies are needed to validate these findings with larger datasets and assess additional MRI sequences and radiomic features.
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Affiliation(s)
| | | | - Saud Nayef Aldanyowi
- Department of Surgery, College of Medicine, King Faisal University, AlAhsa, Saudi Arabia
| | - Sami Fadhel Almalki
- Department of Surgery, College of Medicine, King Faisal University, AlAhsa, Saudi Arabia
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3
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Palova H, Das A, Pokorna P, Bajciova V, Pavelka Z, Jezova M, Pal K, Dimayacyac JR, Negm L, Stengs L, Bianchi V, Vejmelkova K, Noskova K, Jarosova M, Mejstrikova S, Mudry P, Kyr M, Merta T, Tinka P, Drabova K, Aulicka S, Jugas R, Tabori U, Slaby O, Sterba J. Precision immuno-oncology approach for four malignant tumors in siblings with constitutional mismatch repair deficiency syndrome. NPJ Precis Oncol 2024; 8:110. [PMID: 38773265 PMCID: PMC11109258 DOI: 10.1038/s41698-024-00597-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 05/03/2024] [Indexed: 05/23/2024] Open
Abstract
Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies.
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Affiliation(s)
- Hana Palova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Anirban Das
- Division of Haematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Petra Pokorna
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Viera Bajciova
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Zdenek Pavelka
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Marta Jezova
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Karol Pal
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Jose R Dimayacyac
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Logine Negm
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Lucie Stengs
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Vanessa Bianchi
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Klara Vejmelkova
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Kristyna Noskova
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
- Clinical Pharmacy Section of Hospital Pharmacy, University Hospital Brno, Brno, Czech Republic
| | - Marie Jarosova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Sona Mejstrikova
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Peter Mudry
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Michal Kyr
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Tomas Merta
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Pavel Tinka
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic
| | - Klara Drabova
- Institute of Medical Genetics and Genomics, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Stefania Aulicka
- Department of Pediatric Neurology, University Hospital Brno, and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Robin Jugas
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Uri Tabori
- Division of Haematology Oncology, The Hospital for Sick Children, Toronto, ON, Canada
- The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
| | - Jaroslav Sterba
- Department of Pediatric Oncology, University Hospital Brno, and Faculty of Medicine, ERN PaedCan Center, Masaryk University, Brno, Czech Republic.
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Imyanitov EN, Kuligina ES, Sokolenko AP, Suspitsin EN, Yanus GA, Iyevleva AG, Ivantsov AO, Aleksakhina SN. Hereditary cancer syndromes. World J Clin Oncol 2023; 14:40-68. [PMID: 36908677 PMCID: PMC9993141 DOI: 10.5306/wjco.v14.i2.40] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.
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Affiliation(s)
- Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Ekaterina S Kuligina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Anna P Sokolenko
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Evgeny N Suspitsin
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Grigoriy A Yanus
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Aglaya G Iyevleva
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Alexandr O Ivantsov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
| | - Svetlana N Aleksakhina
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia
- Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, St.-Petersburg 194100, Russia
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Wang X, Langevin AM, Houghton PJ, Zheng S. Genomic disparities between cancers in adolescent and young adults and in older adults. Nat Commun 2022; 13:7223. [PMID: 36433963 PMCID: PMC9700745 DOI: 10.1038/s41467-022-34959-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 11/11/2022] [Indexed: 11/27/2022] Open
Abstract
Cancers cause significant mortality and morbidity in adolescents and young adults (AYAs), but their biological underpinnings are incompletely understood. Here, we analyze clinical and genomic disparities between AYAs and older adults (OAs) in more than 100,000 cancer patients. We find significant differences in clinical presentation between AYAs and OAs, including sex, metastasis rates, race and ethnicity, and cancer histology. In most cancer types, AYA tumors show lower mutation burden and less genome instability. Accordingly, most cancer genes show less mutations and copy number changes in AYAs, including the noncoding TERT promoter mutations. However, CTNNB1 and BRAF mutations are consistently overrepresented in AYAs across multiple cancer types. AYA tumors also exhibit more driver gene fusions that are frequently observed in pediatric cancers. We find that histology is an important contributor to genetic disparities between AYAs and OAs. Mutational signature analysis of hypermutators shows stronger endogenous mutational processes such as MMR-deficiency but weaker exogenous processes such as tobacco exposure in AYAs. Finally, we demonstrate a panoramic view of clinically actionable genetic events in AYA tumors.
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Affiliation(s)
- Xiaojing Wang
- grid.267309.90000 0001 0629 5880Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880MD Anderson Mays Cancer Center, UT Health San Antonio, San Antonio, TX USA
| | - Anne-Marie Langevin
- grid.267309.90000 0001 0629 5880MD Anderson Mays Cancer Center, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880Department of Pediatrics, UT Health San Antonio, San Antonio, TX USA
| | - Peter J. Houghton
- grid.267309.90000 0001 0629 5880Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880MD Anderson Mays Cancer Center, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX USA
| | - Siyuan Zheng
- grid.267309.90000 0001 0629 5880Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX USA ,grid.267309.90000 0001 0629 5880MD Anderson Mays Cancer Center, UT Health San Antonio, San Antonio, TX USA
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Cabezas-Camarero S, Pérez-Alfayate R, García-Barberán V, Polidura MC, Gómez-Ruiz MN, Casado-Fariñas I, Subhi-Issa IA, Hernández JCP, Garre P, Díaz-Millán I, Pérez-Segura P. Durable benefit and change in TCR clonality with nivolumab in a Lynch syndrome-associated glioma. Ther Adv Med Oncol 2022; 14:17588359221100863. [PMID: 35694191 PMCID: PMC9185004 DOI: 10.1177/17588359221100863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 04/28/2022] [Indexed: 11/15/2022] Open
Abstract
Germline replication-repair deficient (gRRD) gliomas are exceptional events, and only a few of them have been treated with immune checkpoint inhibitors (ICIs). Contrary to sporadic gliomas, where ICIs have failed to show any objective benefit, the very few patients with gRRD gliomas treated with ICIs to date seem to benefit from programmed-death-1 (PD-1) inhibitors, such as nivolumab or pembrolizumab, either in terms of durable responses or in terms of survival. T-cell immunohistochemistry (IHC) and T-cell receptor (TCR) repertoire using high-throughput next-generation sequencing (NGS) with the Oncomine TCR-Beta-SR assay (Thermo Fisher Scientific) were analyzed in pre- and post-nivolumab tumor biopsies obtained from a patient with a Lynch syndrome-associated glioma due to a germline pathogenic hMLH1 mutation. The aim was to describe changes in the T-cell quantity and clonality after treatment with nivolumab to better understand the role of acquired immunity in gRRD gliomas. The patient showed a slow disease progression and overall survival of 10 months since the start of anti-PD-1 therapy with excellent tolerance. A very scant T-cell infiltrate was observed both at initial diagnosis and after four cycles of nivolumab. The drastic change observed in TCR clonality in the post-nivolumab biopsy may be explained by the highly spatial and temporal heterogeneity of glioblastomas. Despite the durable benefit from nivolumab, the scant T-cell infiltrate possibly explains the lack of objective response to anti-PD-1 therapy. The major change in TCR clonality observed after nivolumab possibly reflects the evolving molecular heterogeneity in a highly pre-treated disease. An in-deep review of the available literature regarding the role of ICIs in both sporadic and gRRD gliomas was conducted.
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Affiliation(s)
- Santiago Cabezas-Camarero
- Medical Oncology Department, Hospital Clínico
Universitario San Carlos, Instituto de Investigación Sanitaria San Carlos
(IdISSC), Calle Profesor Martin Lagos S/N, 28040, Madrid, Spain
| | - Rebeca Pérez-Alfayate
- Department of Neurosurgery, Instituto de
Neurociencias, Hospital Clínico Universitario San Carlos, Madrid,
Spain
| | - Vanesa García-Barberán
- Molecular Oncology Laboratory, Medical Oncology
Department, Hospital Clínico Universitario San Carlos, Instituto de
Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | | | | | | | | | | | - Pilar Garre
- Molecular Diagnosis Unit, Clinical Chemistry
Department, IML, Instituto de Investigación Sanitaria San Carlos (IdISSC),
Hospital Clinico Universitario San Carlos, Madrid, Spain
| | - Isabel Díaz-Millán
- Research Nurse, Medical Oncology Department,
Hospital Clínico Universitario San Carlos, Madrid, Spain
| | - Pedro Pérez-Segura
- Medical Oncology Department, Hospital Clínico
Universitario San Carlos, Instituto de Investigación Sanitaria San Carlos
(IdISSC), Madrid, Spain
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7
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Delayed Effect of Dendritic Cells Vaccination on Survival in Glioblastoma: A Systematic Review and Meta-Analysis. Curr Oncol 2022; 29:881-891. [PMID: 35200574 PMCID: PMC8870360 DOI: 10.3390/curroncol29020075] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/26/2022] [Accepted: 02/01/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Dendritic cell vaccination (DCV) strategies, thanks to a complex immune response, may flare tumor regression and improve patients’ long-term survival. This meta-analysis aims to assess the efficacy of DCV for newly diagnosed glioblastoma patients in clinical trials. Methods: The study databases, including PubMed, Web of Knowledge, Google Scholar, Scopus, and Cochrane, were searched by two blinded investigators considering eligible studies based on the following keywords: “glioblastoma multiforme”, “dendritic cell”, “vaccination”, “immunotherapy”, “immune system”, “immune response”, “chemotherapy”, “recurrence”, and “temozolomide”. Among the 157 screened, only 15 articles were eligible for the final analysis. Results: Regimens including DCV showed no effect on 6-month progression-free survival (PFS, HR = 1.385, 95% CI: 0.822–2.335, p = 0.673) or on 6-month overall survival (OS, HR = 1.408, 95% CI: 0.882–2.248, p = 0.754). In contrast, DCV led to significantly longer 1-year OS (HR = 1.936, 95% CI: 1.396–2.85, p = 0.001) and longer 2-year OS (HR = 3.670, 95% CI: 2.291–5.879, p = 0.001) versus control groups. Hence, introducing DCV could lead to increased 1 and 2-year survival of patients by 1.9 and 3.6 times, respectively. Conclusion: Antitumor regimens including DCV can effectively improve mid-term survival in patients suffering glioblastoma multiforme (GBM), but its impact emerges only after one year from vaccination. These data indicate the need for more time to achieve an anti-GBM immune response and suggest additional therapeutics, such as checkpoint inhibitors, to empower an earlier DCV action in patients affected by a very poor prognosis.
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Abidi A, Gorris MAJ, Brennan E, Jongmans MCJ, Weijers DD, Kuiper RP, de Voer RM, Hoogerbrugge N, Schreibelt G, de Vries IJM. Challenges of Neoantigen Targeting in Lynch Syndrome and Constitutional Mismatch Repair Deficiency Syndrome. Cancers (Basel) 2021; 13:2345. [PMID: 34067951 PMCID: PMC8152233 DOI: 10.3390/cancers13102345] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/11/2022] Open
Abstract
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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Affiliation(s)
- Asima Abidi
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - Mark A. J. Gorris
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - Evan Brennan
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - Marjolijn C. J. Jongmans
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (M.C.J.J.); (D.D.W.); (R.P.K.)
- Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Dilys D. Weijers
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (M.C.J.J.); (D.D.W.); (R.P.K.)
| | - Roland P. Kuiper
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (M.C.J.J.); (D.D.W.); (R.P.K.)
- Department of Genetics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Richarda M. de Voer
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.M.d.V.); (N.H.)
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (R.M.d.V.); (N.H.)
| | - Gerty Schreibelt
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (A.A.); (M.A.J.G.); (E.B.); (G.S.)
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
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9
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Leelatian N, Hong CS, Bindra RS. The Role of Mismatch Repair in Glioblastoma Multiforme Treatment Response and Resistance. Neurosurg Clin N Am 2021; 32:171-180. [PMID: 33781500 DOI: 10.1016/j.nec.2020.12.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Mismatch repair (MMR) is a highly conserved DNA repair pathway that is critical for the maintenance of genomic integrity. This pathway targets base substitution and insertion-deletion mismatches, which primarily arise from replication errors that escape DNA polymerase proof-reading function. Here, the authors review key concepts in the molecular mechanisms of MMR in response to alkylation damage, approaches to detect MMR status in the clinic, and the clinical relevance of this pathway in glioblastoma multiforme treatment response and resistance.
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Affiliation(s)
- Nalin Leelatian
- Department of Pathology, Yale School of Medicine, 310 Cedar Street LH 108, New Haven, CT 06510, USA
| | - Christopher S Hong
- Department of Neurosurgery, Yale School of Medicine, 333 Cedar Street Tompkins 4, New Haven, CT 06510, USA
| | - Ranjit S Bindra
- Department of Therapeutic Radiology, Yale School of Medicine, 333 Cedar Street Hunter 2, New Haven, CT 06510, USA.
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Xie T, Feng Q, Li Z, Lu M, Li J, Lizaso A, Xiang J, Zhang L, Shen L, Peng Z. Heterogeneous constitutional mismatch repair deficiency with MSH6 missense mutation clinically benefits from pembrolizumab and regorafenib combination therapy: a case report and literature review. Hered Cancer Clin Pract 2021; 19:7. [PMID: 33422121 PMCID: PMC7797131 DOI: 10.1186/s13053-021-00165-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 01/02/2021] [Indexed: 11/22/2022] Open
Abstract
Background Germline DNA mismatch repair (MMR) gene aberrations are associated with colorectal cancer (CRC) predisposition and high tumor mutation burden (TMB-H), with increased likelihood of favorable response to immune checkpoint inhibitors (ICIs). Case presentation We present a 32-year old male patient diagnosed with constitutional MMR deficiency (CMMRD) CRC whose MMR immunohistochemistry (IHC) revealed inconsistent results from two tumor blocks. Targeted sequencing of two tumor specimens used in MMR-IHC and plasma-derived circulating tumor DNA consistently revealed the detection of bi-allelic germline MSH6 c.3226C > T (p.R1076C) mutation, TMB-H as well as the genetic heterogeneity of the tumor samples. Unexpectedly, both blocks were microsatellite stable (MSS) after PCR confirmation. Interestingly, the patient failed to show response to ICI monotherapy or dual therapy, but clinically benefitted from combined therapy of ICI pembrolizumab plus multi-kinase inhibitor regorafenib. Conclusion Our case reported a CMMRD patient with heterogeneous MMR results who showed complicated response to ICIs, highlighting the importance of accurate diagnosis using targeted sequencing with multiple specimens to reveal the possible mechanism of response to ICI in patients with CMMRD. Supplementary Information The online version contains supplementary material available at 10.1186/s13053-021-00165-2.
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Affiliation(s)
- Tong Xie
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Qin Feng
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China
| | | | | | - Lu Zhang
- Burning Rock Biotech, Guangzhou, 510300, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China.
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Bloom M, Maciaszek JL, Clark ME, Pui CH, Nichols KE. Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia. Expert Rev Hematol 2020; 13:55-70. [PMID: 31657974 PMCID: PMC10576863 DOI: 10.1080/17474086.2020.1685866] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 10/24/2019] [Indexed: 12/11/2022]
Abstract
Introduction: Historically, the majority of childhood cancers, including acute lymphoblastic leukemia (ALL), were not thought to have a hereditary basis. However, recent germline genomic studies have revealed that at least 5 - 10% of children with cancer (and approximately 3 - 4% of children with ALL) develop the disease due to an underlying genetic predisposition.Areas covered: This review discusses several recently identified ALL predisposing conditions and provides updates on other more well-established syndromes. It also covers topics related to the evaluation and management of children and family members at increased ALL risk.Expert opinion: Germline predisposition is gaining recognition as an important risk factor underlying the development of pediatric ALL. The challenge now lies in how best to capitalize on germline genetic information to improve ALL diagnosis, treatment, and perhaps even prevention.
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Affiliation(s)
- Mackenzie Bloom
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Jamie L. Maciaszek
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Mary Egan Clark
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Ching-Hon Pui
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Kim E. Nichols
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
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Perrino M, Cooke-Barber J, Dasgupta R, Geller JI. Genetic predisposition to cancer: Surveillance and intervention. Semin Pediatr Surg 2019; 28:150858. [PMID: 31931963 DOI: 10.1016/j.sempedsurg.2019.150858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer is one of the leading causes of early mortality for children and adolescents. Identifiable genetic cancer predisposition conditions account for a growing proportion of pediatric and adolescent cancer, likely due to increasing knowledge about various predisposition conditions, more widespread cancer genetic counseling, and available diagnostics. Greater awareness, data-driven surgical intervention and clinical surveillance can help facilitate cancer prevention and early detection at cancer stages more amenable to cure. An extensive literature review of published studies and expert opinion with consensus guidelines are reviewed. Specific syndromes where genetics, imaging and surgical intervention are utilized to benefit affected patients and families are presented. In many tumor predisposition syndromes, the underlying genetic diagnosis is made concurrently, or after, malignancy is identified. Improved recognition of underlying predispositions, along with appropriate surgical interventions and imaging surveillance should lead to increased patient survival.
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Affiliation(s)
- Melissa Perrino
- Department of Pediatrics, Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States
| | - Jo Cooke-Barber
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States
| | - Roshni Dasgupta
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States
| | - James I Geller
- Department of Pediatrics, Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, United States.
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