Constitutional Mismatch Repair Deficiency Syndrome Research Articles

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Immune Checkpoint Inhibition in Pediatric Oncology Patients: A Single-Institution Experience

Immunotherapy has emerged as a promising treatment approach in oncology, as it is specifically designed to boost the strength and accuracy of the immune system, allowing it to target tumor cells but spare non-tumor tissue. This treatment not only demonstrates potential for improved clinical outcomes but may also be associated with fewer adverse effects compared to traditional therapies. Despite its early success, the application of immunotherapy has largely been limited to adult cancer patients, with slow adoption noted in the treatment of pediatric cancer patients. Our objective is to demonstrate a single institution’s experience with immunotherapy in pediatric cancer patients and to discuss the use of these treatment modalities in this unique patient population. We performed a retrospective chart review and identified patients who received immune checkpoint inhibitors (ICIs) and/or underwent immunohistochemistry (IHC) testing for programmed death ligand 1 (PD-L1), quantification of tumor mutational burden (TMB), and classification of microsatellite instability (MSI) status. In total, we identified seven pediatric cancer patients who received therapy with ICIs. Four of these patients demonstrated positive PD-L1 expression, high TMB, and/or MSI-high status. These patients were treated with nivolumab alone or in combination with ipilimumab or brentuximab. The diagnoses included: multifocal epithelioid and spindle cell hemangioma (n = 1); metastatic melanoma (n = 2); histiocytic sarcoma (n = 1); rectal adenocarcinoma in the setting of constitutional mismatch repair deficiency syndrome (CMMRD) (n = 1); and Hodgkin lymphoma (n = 2). The patients received between four and nineteen cycles of immunotherapy. Immunotherapy-related adverse events included: mild allergic reaction; prodromal symptoms; anemia; neutropenia; transaminitis; endocrinopathies; and self-limiting neuritis. Of the seven patients, three are still being treated with immunotherapy (the patients with rectal adenocarcinoma, metastatic melanoma, and multifocal epithelioid and spindle cell hemangioma) with positive treatment responses observed on imaging, one is being treated with other modalities (the patient with Hodgkin lymphoma), two have achieved remission (the patients with metastatic melanoma and Hodgkin lymphoma), and one has relapsed (the patient with histiocytic sarcoma). The three patients who completed their immunotherapy regimens have been followed for 1 month, 4 months, and 10 months, respectively. This report of a single-institution experience with immunotherapy in pediatric cancer patients highlights the positive impact immunotherapy can have, especially when utilized to treat relapsed/refractory malignancies, as tumor regression or stabilization of disease burden was achieved in six of the patients described (CR = 2; PR = 4). Further research is needed to accurately identify pediatric oncology patients who could benefit from immunotherapy.

Constitutional mismatch repair deficiency syndrome as a cause of numerous malignancies in a teenage patient - a case report

Constitutional mismatch repair deficiency syndrome as a cause of numerous malignancies in a teenage patient - a case report

Abstract C086: NP1867, a potent, selective, covalent small molecule inhibitor of DNA Mismatch Repair (MMR) protein PMS2, functionally inhibits MMR in cells and elicits COSMIC mutational signatures consistent with MMR-deficient patient samples

Abstract Two complementary mechanisms safeguard genome fidelity during DNA replication: DNA polymerase proofreading and DNA mismatch repair (MMR). DNA polymerase proofreading or MMR deficiencies can occur independently or, more rarely, simultaneously; loss of function of either or both pathways leads to the accumulation of DNA mutations. Lynch Syndrome is caused by mono-allelic germline mutations in MMR genes MLH1, MSH2, MSH6 or PMS2. Gene expression from the wild-type allele elicits sufficient MMR activity until a second hit somatic mutation inactivates the wild-type allele leading to MMR deficiency (MMR-d). Constitutional mismatch repair deficiency (CMMRD) syndrome is an inherited early onset cancer predisposition syndrome resulting from biallelic germline mutations in MLH1, MSH2, MSH6 or PMS2. MMR-d cancers are commonly and typically characterized by accumulation of single nucleotide variants (SNVs) and insertions or deletions (indels) amongst repetitive DNA sequences - microsatellite instability (MSI); importantly, such mutations occur at higher rates in genetically unstable tumour cells under replicative stress than in normal cells. Cancers that harbour &amp;gt;40% microsatellite variations (positive for two or more of five clinically tested microsatellite markers) are described as MSI-high (MSI-H). Importantly, MMR-d, MSI-H tumours are now eligible for immune checkpoint therapy, irrespective of tissue type, providing substantial patient benefit and a major advance in cancer treatment. This clinical context is consistent with the hypothesis that MMR-d elicits an immunogenic state. However, there is an unmet need for chemical tools to explore the role of therapeutic MMR inhibition alongside immune checkpoint blockade. Here, for the first time, we demonstrate that NP1867 is a potent, selective small molecule inhibitor of the Gyrase, Hsp90, Histidine Kinase, MutL (GHKL) family endonuclease PMS1 Homolog 2, Mismatch Repair System Component (PMS2). We demonstrate by biochemical, biophysical, and protein-ligand X-ray crystallographic methods that NP1867 binds irreversibly to the ATP binding site of the N-terminal ATPase domain of PMS2. NP1867 displays potent binding to PMS2 in a NanoBRET cellular target engagement assay and inhibits MMR activity in cell-based assays of MMR-dependent DNA repair. NP1867 displays minimal off-target binding in broad biochemical screening panels including kinases and ATPases. Treatment of MMR-proficient, colorectal cancer cell lines with NP1867 increases tumour mutational burden and generates COSMIC mutational signatures consistent with MMR-d patient samples demonstrating, for the first time, that acute inhibition of PMS2 with a small molecule phenocopies the epigenetic silencing and/or genetic loss of MMR observed in patients. We characterise cell- and tissue-based target engagement, and in vivo pharmacokinetic and pharmacodynamic properties of NP1867 to inform optimal use by the research community for further exploring PMS2 and MMR function. Citation Format: Julian Blagg, Philippe Riou, Alexia Hervieu, Eleonora Piumatti, Giuseppe Rospo, Sasi Arunachalam, Bettina Meier, Sam Weeks, Maria Rodriguez, Kalpesh Parmar, Pradip Patel, Adam Peall, Paige Tongue, Tess McLaren, Robert Workman, Ruzica Bago, Stuart Robjohns, Rebecca Beaumont, Mike Briggs, Gareth Langley, Charles Nichols, David Clark, Paul Winship, Benoit Rousseau, Matthew Baker, Martin Drysdale, Giovanni Germano, Alberto Bardelli. NP1867, a potent, selective, covalent small molecule inhibitor of DNA Mismatch Repair (MMR) protein PMS2, functionally inhibits MMR in cells and elicits COSMIC mutational signatures consistent with MMR-deficient patient samples [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C086.

CMMRD-associated embryonic rhabdomyosarcoma in a child. Clinical case with literature review

Introduction. Hereditary disorders in the DNA repair system can lead to the development of malignant neoplasms in childhood. DNA constitutional mismatch repair deficiency syndrome (CMMRD) is a very rare genetic autosomal recessive disorder caused by homozygous mutations in one of the four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). The frequency of occurrence is 0.0000001 of the adult and child population. For now about 150 observations have been published in the world literature. The prognosis for CMMRD syndrome is extremely unfavorable. The spectrum of tumors that make up the CMMRD syndrome is very wide, and includes mainly malignant brain tumors, tumors of the digestive tract, hematological malignancies, embryonic tumors, all of which develop in childhood.The purpose of the study is to report a case of CMMRD-associated embryonic rhabdomyosarcoma in a 3-year-old child.Conclusions. A review of the literature and the clinical case we have described show that rhabdomyosarcoma belongs to the tumor spectrum of the CMMRD syndrome. An immunohistochemical study revealed an isolated loss of PMS2 gene expression. Taking into account the clinical course of the CMMRD syndrome, a thorough study of the family history in patients with rhabdomyosarcoma is recommended, as well as a molecular genetic study, including the search for germinal mutations in genes in the DNA repair system and the assessment of microsatellite instability in the material of the tumor tissue. The clinical symptoms of CMMRD syndrome are nonspecific and depend on the morphological variant of the primary tumor. Distinctive molecular genetic features of this syndrome are: homozygous mutations with loss of function of the germline genes of the MMR system (mismatch repair) (MLH1, MSH2, MSH6 or PMS2).

Diffuse Pediatric-Type High-Grade Glioma H3-/IDH-wildtype with MYCN Deletion and Constitutional Mismatch Repair Deficiency: Case Presentation

Diffuse pediatric-type high-grade glioma H3-wildtype and IDH-wildtype (pHGG H3/IDH WT) is a heterogeneous entity that is currently defined by a combination of highly malignant morphology, glial or primitive neuroectodermal differentiation, and a number of molecular features. Depending on the DNA methylation profile in pHGG H3/IDH WT, three molecular subgroups are distinguished, one of which (pHGG MYCN) is characterized by amplification of the indicated gene. We report a unique case of pHGG H3/IDH WT in a 19-year-old girl with a deletion of the MYCN gene and constitutional mismatch repair deficiency syndrome.

Glioma arising in the setting of mismatch repair deficiency-rare or are we missing it?

Germline mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) can be mono-allelic or biallelic, resulting in a Lynch syndrome (LS) or constitutional mismatch repair deficiency (CMMRD) syndrome respectively. Glioma arising in the setting of MMR deficiency is uncommon. We describe two pediatric patients with high-grade glioma (HGG) and associated MMR protein deficiency. On histomorphology both cases showed HGG with astrocytic morphology and prominent multinucleated tumor cells. On immunohistochemistry, the first case was negative for IDH1 p.R132H showed loss of ATRX and p53 positivity. The second case was positive for IDH1 p.R132H and p53, but showed retained expression of ATRX. The histomorphology in both cases and additionally IDH mutation with retained ATRX in the second case, prompted us to test for MMR protein deficiency which was carried out by immunohistochemistry (IHC). One case revealed an immunostaining pattern suggestive of CMMRD while the other was suggestive of LS. Both the cases showed good response to surgery and radio-chemotherapy in the follow-up available. Our cases highlight the importance of testing for MMR proteins by simple IHC, in the setting of appropriate clinical scenario, histopathological and immunohistochemical findings. The recognition of these tumors is extremely important to guide further treatment and prompt family screening.

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer.

Genome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed. To better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization. The organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node. The established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.

Diagnosis and Management of Constitutional Mismatch Repair Deficiency Syndrome.

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive genetic disorder that has little more than 200 total cases reported as of 2020. Whereas a single mutation in genes responsible for mismatch repair causes the autosomal dominant Lynch syndrome (LS), CMMRD is caused by biallelic heterozygous defects: distinct deleterious mutations on each allele for a single gene. As the disease is exceedingly rare and may present via a wide variety of signs, including neurofibromatosis type 1- and Lynch Syndrome-associated malignancies, diagnosis and subsequent surveillance are complex with suggested methods published by the International Replication Repair Deficiency Consortium. We report here the history and management of a patient whose newly diagnosed CMMRD was managed with both curative and prophylactic surgical treatment.

Resolving inherited and de novo germline predisposing sequence variants by means of whole exome trio analyses in childhood hematological malignancies.

Molecular screening tools have significantly eased the assessment of potential germline susceptibility factors that may underlie the development of pediatric malignancies. Most of the hitherto published studies utilize the comparative analyses of the respective patients' germline and tumor tissues for this purpose. Since this approach is not able to discriminate between de novo and inherited sequence variants, we performed whole exome trio analyses in a consecutive series of 131 children with various forms of hematologic malignancies and their parents. In total, we identified 458 de novo variants with a range from zero to 28 (median value = 3) per patient, although most of them (58%) had only up to three per exome. Overall, we identified bona fide cancer predisposing alterations in five of the investigated 131 (3.8%) patients. Three of them had de novo pathogenic lesions in the SOS1, PTPN11 and TP53 genes and two of them parentally inherited ones in the STK11 and PMS2 genes that are specific for a Peutz-Jeghers and a constitutional mismatch repair deficiency (CMMRD) syndrome, respectively. Notwithstanding that we did not identify a disease-specific alteration in the two cases with the highest number of de novo variants, one of them developed two almost synchronous malignancies: a myelodysplastic syndrome and successively within two months a cerebral astrocytoma. Moreover, we also found that the rate of de novo sequence variants in the offspring increased especially with the age of the father, but less so with that of the mother. We therefore conclude that trio analyses deliver an immediate overview about the inheritance pattern of the entire spectrum of sequence variants, which not only helps to securely identify the de novo or inherited nature of genuinely disease-related lesions, but also of all other less obvious variants that in one or the other way may eventually advance our understanding of the disease process.

Unexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding.

The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface.

Acute lymphoblastic lymphoma/leukaemia in a dysplastic rectal polyp

Constitutional mismatch repair deficiency (CMMRD) syndrome is a recently defined syndrome caused by biallelic inheritance of mutated PMS2, MLH1, MSH2 or MSH6 genes that predisposes those affected to developing malignancies of the central nervous system, gastrointestinal tract and haematological system in childhood and adolescence. Outcomes are generally poor, and risk of synchronous and metachronous disease is high. As a prelude to learning about CMMRD, we present this case where we diagnosed acute lymphoblastic leukaemia/lymphoma in a tubular adenoma from a 9-year-old female.

DNAR-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON HIGH GRADE GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASKFORCE

Abstract Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation and aggressive cancers that are resistant to chemoradiation yet sensitive to immunotherapy. MMRD mutations can occur somatically or be inherited as a part of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD). Although MMRD affects children, adolescents and young adults (CAYA, ages 0-40) with gliomas, its prevalence and impact of germline inheritance is unknown. Given that high microsatellite instability (MSI) is a key characteristic of MMRD, we previously developed a robust low-coverage whole genome-based tool to quantify MSI, which allows for accurate MMRD detection. We are therefore performing a large-scale MMRD screen of CAYA high grade gliomas (HGGs) and utilizing data from the International Replication Repair Deficiency Consortium (IRRDC) to determine the impact of germline mutations in MMRD gliomas. Ongoing data on 346 HGGs from CAYA patients reveals that MMRD is identified in 6% of HGGs and is not present in tumors with pediatric type alterations. Moreover, of MMRD tumors with IDH1 mutations, none harbor 1p/19q co-deletions. Of patients with available information, all are diagnosed with Lynch Syndrome (69%) or CMMRD (31%), with all Lynch Syndrome diagnoses occurring in patients above 18 years of age. Complementary data from the IRRDC on 113 MMRD patients with gliomas reveal that the median age of glioma is 9.7 and 17.5 years in CMMRD and Lynch Syndrome, respectively (p &amp;lt; 0.001). Strikingly, CMMRD gliomas are enriched for secondary polymerase mutations (60%, p &amp;lt; 0.001) and exhibit ultra-hypermutation, while MMRD gliomas with Lynch Syndrome are enriched for IDH1 mutations (32%, p &amp;lt; 0.025) and harbor a lower mutational burden. Our data reveal a high prevalence of MMRD in CAYA HGGs with alarming impact of germline predisposition. These data can support universal screening for MMRD in high grade glioma diagnostics and identify patients for precision therapeutics.

Clinical and molecular features of pediatric cancer patients with Lynch syndrome.

The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD). We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies. There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at-risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis. Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD.

HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome

Abstract PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.

Merged testing for colorectal cancer syndromes and re-evaluation of genetic variants improve diagnostic yield: Results from a nationwide prospective cohort.

Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease‐causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH‐associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent‐onset CRC and polyposis had biallelic disease‐causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post‐study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield.

Diffuse Large B-Cell Lymphoma, Epstein–Barr Virus -Positive Kappa Monotypic Plasma Cell Proliferation and Invasive Carcinoma, Developing in a Child With Defective Mismatch Repair

Constitutional mismatch repair deficiency (CMMRD) syndrome is characterized by biallelic mutations in a mismatch repair gene and is associated with development of childhood cancers and symptoms resembling neurofibromatosis type 1, like café-au-lait spots. We describe the extremely rare case of a 12-year-old male presenting with several light brown macular lesions on the skin, gastrointestinal diffuse large B-cell lymphoma, adenomatous polyposis throughout the gastrointestinal tract and an intra-abdominal invasive carcinoma derived from upper gastrointestinal system. All neoplasia, as well as normal tissues, showed loss of Msh6 expression with immunohistochemistry. Molecular studies showed pathogenic homozygous p.F1088Sfs*2 mutation in MSH6. Furthermore, signs consistent with immunodeficiency, namely decreased levels of IgG and IgA in the serum, nodular lymphoid hyperplasia and EBV-associated plasma cell proliferation with monotypic kappa light chain expression in the ileum, were also noted. Our case depicts the phenotypic diversity of CMMRD syndrome and emphasizes its association with immunodeficiency, raising awareness to a feature not widely recognized.

Central Nervous System Tumors in Children.

Central Nervous System Tumors in Children.

Pediatric Hemispheric Glioma

About one-third of pediatric low-grade glioma and a half of pediatric high-grade glioma occur in the cerebrum. Pediatric hemispheric glioma may harbor diagnostic and therapeutically targetable genetic abnormalities, including BRAF V600E, H3.3 G34R/V, FGFR1 alternation, MYB or MYBL1 alternation, and NTRK/ALK/ROS1/MET fusion. In addition, the efficacy of molecular-targeted agents, such as BRAF inhibitors, MEK inhibitors, and NTRK inhibitors, against pediatric glioma with the relevant mutations has been demonstrated in several clinical trials. Furthermore, checkpoint inhibitors are considered a choice of treatment for hypermutated glioma, which is typically observed in patients with constitutional mismatch repair deficiency syndrome. Cancer gene panel testing, approved for insurance coverage in Japan in 2019, has been beneficial to pediatric cancer patients. However, to promote the clinical application of the recent molecular understanding of pediatric neuro-oncology, some issues have to be addressed. Herein, we review the genetic profiles of pediatric hemispheric glioma and introduce the current medical situation of precision medicine for pediatric patients with glioma in Japan.

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Constitutional mismatch repair deficiency (CMMRD) is one of the rare cancer predisposition syndromes. The aim of this study was to evaluate the cerebral developmental venous anomalies in children with central nervous system tumors associated with CMMRD, an area in which there is extremely little experience. Data from children diagnosed with medulloblastoma and high grade central nervous sytem tumor were retrospectively collected. According to the European CMMRD criteria, nine patients were diagnosed as CMMRD syndrome and the others consisted of the group without CMMRD. All radiological examinations of these children were retrospectively reviewed. Whole exome sequencing was performed to index cases` germline DNA. Nine children from four families, six females and three males, were studied. The median age at the first tumor diagnosis was 4.5 years (range, 9 months to 14 years). All CMMRD patients had café au lait spots, but none fulfilled the diagnostic criteria for neurofibromatosis. The patients developed high-grade glial tumor (n: 7) and medulloblastoma (n: 2). The affected genes in the three families were MSH6 [c.478C > T (p.Gln160Ter)], MSH6 [c.2871dupC (p.Phe958LeufsTer5)] and MLH1 [c.236G > A(p.Arg79Lys)], respectively. Seven patients had multiple developmental venous anomalies; six patients had leptomeningeal enhancement; and five patients had cavernomas. None of these findings were present in the group without CMMRD. Constitutional mismatch repair deficiency should be considered when multiple developmental venous anomalies, cavernomas, and leptomeningeal enhancement are detected, especially in patients with café au lait spots.