To assess the associations between congenital abnormalities and pediatric malignancies and evaluate the potential underlying molecular basis by collecting information on pediatric patients with ...cancer and congenital abnormalities.
Tumeur Et Développement is a national, prospective, and retrospective multicenter study recording data of children with cancer and congenital abnormalities. When feasible, blood and tumoral samples are collected for virtual biobanking.
From June 2013 to December 2019, 679 associations between pediatric cancers and congenital abnormalities were recorded. The most represented cancers were central nervous system tumors (n = 139; 20%), leukemia and myelodysplastic syndromes (n = 123; 18.1%), and renal tumors (n = 101; 15%). Congenital abnormalities were not related to any known genetic disorder in 66.5% of cases. In this group, the most common anomaly was intellectual disability (22.3%), followed by musculoskeletal (14.2%) and genitourinary anomalies (12.4%). Intellectual disability was mostly associated with hematologic malignancies. Embryonic tumors (neuroblastoma, Wilms tumor, and rhabdomyosarcoma) were associated with consistent abnormalities, sometimes with a close anatomical neighborhood between the abnormality and the neoplasm.
In the first Tumeur Et Développement analysis, 3 major themes have been identified: (1) germline mutations with or without known cancer predisposition, (2) postzygotic events responsible for genomic mosaicism, (3) coincidental associations. New pathways involved in cancer development need to be investigated to improve our understanding of childhood cancers.
Hepatoblastomas (HB) display heterogeneous cellular phenotypes that influence the clinical outcome, but the underlying mechanisms are poorly understood. Here, we use a single-cell multiomic strategy ...to unravel the molecular determinants of this plasticity. We identify a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.
Abstract
Pediatric liver tumors are very rare tumors with the most common diagnosis being hepatoblastoma. While hepatoblastomas are predominantly sporadic, around 15% of cases develop as part of ...predisposition syndromes such as Beckwith-Wiedemann (11p15.5 locus altered). Here, we identify mosaic genetic alterations of 11p15.5 locus in the liver of hepatoblastoma patients without a clinical diagnosis of Beckwith-Wiedemann syndrome. We do not retrieve these alterations in children with other types of pediatric liver tumors. We show that mosaic 11p15.5 alterations in liver FFPE sections of hepatoblastoma patients display
IGF2
overexpression and
H19
downregulation together with an alteration of the liver zonation. Moreover, mosaic livers’ microenvironment is enriched in extracellular matrix and angiogenesis. Spatial transcriptomics and single-nucleus RNAseq analyses identify a 60-gene signature in 11p15.5 altered hepatocytes. These data provide insights for 11p15.5 mosaicism detection and its functional consequences during the early steps of carcinogenesis.
Hepatoblastoma (HB) is the most common liver cancer in children. We aimed to characterize HB related to APC (Adenomatous Polyposis Coli) germline mutation (APC-HB). This French multicentric ...retrospective study included 12 APC-HB patients under 5 at diagnosis. Clinical features of APC-HB were compared to the French SIOPEL2-3 cohort of HB patients. Molecular and histopathological analyses of APC-HB were compared to 15 consecutive sporadic HB treated at Bicêtre hospital from 2013 to 2015 (non-APC-HB). APC-HB patients have a peculiar spectrum of germline APC mutations, with no events in the main hotspot of classical APC mutations at codon 1309 (P < .05). Compared to sporadic HB, they have similar clinical features including good prognosis since all patients are alive in complete remission at last follow-up. APC-HB are mostly well-limited tumors with fetal predominance and few mesenchymal components. All APC-HB have an activated Wnt/β-catenin pathway without CTNNB1 mutation, confirming that germline APC and somatic CTNNB1 mutations are mutually exclusive (P < .001). Pathological reviewing identified massive intratumor tertiary lymphoid structures (TLS) containing both lymphocytes and antigen-presenting cells in all 11 APC-HB cases who received cisplatin-based neoadjuvant chemotherapy but not in five pre-chemotherapy samples (four paired biopsies and one patient resected without chemotherapy), indicating that these TLS are induced by chemotherapy (P < .001). Conclusion: APC-HB show a good prognosis, they are all infiltrated by cisplatin-induced TLS, a feature only retrieved in a minority of non-APC-HB. This suggests that APC inactivation can synergize with cisplatin to induce an immunogenic cell death that initiates an anti-tumor immune response.
Several case reports suggest that rituximab (RTX) could be effective in steroid-dependent nephrotic syndrome, but RTX efficacy has not yet been studied in a series of patients. Safety and efficacy of ...RTX were assessed in a multicenter series of 22 patients aged 6.3–22 years with severe steroid-dependent nephrotic syndrome or steroid-resistant but cyclosporin-sensitive idiopathic nephrotic syndrome. Patients were treated with two to four infusions of RTX. Seven patients were nephrotic at the time of RTX treatment. Peripheral B cells were depleted in all subjects. Remission was induced in three of the seven proteinuric patients. One or more immunosuppressive (IS) treatments could be withdrawn in 19 patients (85%), with no relapse of proteinuria and without increasing other IS drugs. RTX was effective in all patients when administered during a proteinuria-free period in association with other IS agents. When relapses occurred, they were always associated with an increase in CD19 cell count. Adverse effects were observed in 45% of cases, but most of them were mild and transient. This study suggests that RTX could be an effective treatment for severe steroid-dependent nephrotic syndrome.
Few studies have investigated the seasonal patterns of embryonal tumours. Based on data from the French National Registry of Childhood Cancers, the present study aimed to investigate seasonal ...variations in embryonal tumour incidence rates by month of birth and by month of diagnosis. The study included 6635 primary embryonal tumour cases diagnosed before the age of 15 years over the period 2000‐2015 in mainland France. Assuming monthly variations in incidence rates were homogeneous over 2000‐2015, we used a Poisson regression model to test for overall heterogeneity in standardised incidence ratios (SIRs) by month of birth or diagnosis. The seasonal scan statistic method was used to detect monthly excesses or deficits of embryonal tumour cases over the whole study period. The annual reproducibility of the observed monthly variations was formally tested. An overall heterogeneity in incidence rates by month of birth was observed for rhabdomyosarcoma in boys only. Based on the month of diagnosis, a seasonality was evidenced for unilateral retinoblastoma, with a lower incidence rate in the summer (SIRJul‐Aug = 0.68, 95% CI = 0.52‐0.87), whilst the incidence rate of rhabdomyosarcoma tended to be lower in August (SIRAug = 0.68, 95% CI = 0.52‐0.89). No seasonality was detected for the other embryonal tumour groups by month of birth or month of diagnosis. This study is one of the largest to have investigated the seasonality of childhood embryonal tumours. The study showed a seasonal variation in the incidence rates by month of diagnosis for unilateral retinoblastoma and rhabdomyosarcoma. Our findings are likely to reflect a delay in consultation during the summer months. However, the role of seasonally varying environmental exposures cannot be ruled out.
This study is an in‐depth investigation of seasonal variations in the incidence rates of paediatric embryonal tumours in France (2000‐2015). The results showed a seasonality by month of diagnosis for unilateral retinoblastoma and rhabdomyosarcoma cases, with a lower incidence rate in the summer months. Although our findings are likely to reflect delays in consultation with a specialist, we cannot rule out their being due to seasonally varying environmental exposures. No seasonality by month of birth was observed for the main embryonal tumour groups (neuroblastoma, nephroblastoma, medulloblastoma, rhabdomyosarcoma, retinoblastoma and hepatoblastoma) or specific subgroups considered.
Objective To assess school performance in an unselected group of childhood cancer survivors and study risk factors for impairment. Study design Rates of repeating a grade were compared for patients ...with cancer, their siblings, and the general population. Phone questionnaires were administered to patients about the school career of their child in remission and their siblings. Responses about cancer survivors were compared with those concerning their siblings and various registries provided by the national board of education. The primary outcome was the rate of repeating a grade. Results A total of 148 children in remission with a mean age of 15 ± 5.3 years and a mean follow-up period since diagnosis of 6.3 ± 1.3 years were included. More patients than siblings repeated a grade (33% versus 21%; P = .02), with a mean delay since diagnosis of 2 years. Risk factors were an older age at diagnosis, attending a secondary school, low education level of parents, bone marrow transplantation, cerebral surgery, and physical sequelae. In multivariate analysis, risk for repeating was associated with low educational level of the father, attending secondary school at diagnosis, and requiring school-organized educational support on return to school. Conclusion After cancer, repeating a grade is not an exceptional occurrence, especially for teenagers; follow-up and supportive interventions before returning to school would be beneficial.
Background Primary immunodeficiencies (PIDs) are inherited diseases associated with a considerable increase in susceptibility to infections. It is known that PIDs can also predispose to cancer and ...immune diseases, including allergy, autoimmunity, and inflammation. Objective We aimed at determining the incidence of autoimmunity and inflammation in patients with PIDs. Methods We have retrospectively screened 2183 consecutive cases of PID in the Centre de Référence Déficits Immunitaires Héréditaires registry (CEREDIH; the French national PID registry) for the occurrence of autoimmunity and inflammation. Results One or more autoimmune and inflammatory complications were noted in 26.2% of patients, with a risk of onset throughout the patient's lifetime. The risk of autoimmune cytopenia was at least 120 times higher than in the general population, the risk of inflammatory bowel disease in children was 80 times higher, and the risk of other autoimmune manifestations was approximately 10 times higher. Remarkably, all types of PIDs were associated with a risk of autoimmune and inflammatory complications, although the greatest risk was associated with T-cell PIDs and common variable immunodeficiency. The occurrence of autoimmune disease is a negative prognostic factor for survival. Conclusions Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.
Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and ...renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
Surgery and cisplatin‐based treatment of hepatoblastoma (HB) currently guarantee the survival of 70%‐80% of patients. However, some important challenges remain in diagnosing high‐risk tumors and ...identifying relevant targetable pathways offering new therapeutic avenues. Previously, two molecular subclasses of HB tumors have been described, C1 and C2, with C2 being the subgroup with the poorest prognosis, a more advanced tumor stage, and the worst overall survival rate. An associated 16‐gene signature to discriminate the two tumoral subgroups was proposed, but it has not been transferred into clinical routine. To address these issues, we performed RNA sequencing of 25 tumors and matched normal liver samples from patients. The transcript profiling separated HB into three distinct subgroups named C1, C2A, and C2B, identifiable by a concise four‐gene signature: hydroxysteroid 17‐beta dehydrogenase 6, integrin alpha 6, topoisomerase 2‐alpha, and vimentin, with topoisomerase 2‐alpha being characteristic for the proliferative C2A tumors. Differential expression of these genes was confirmed by quantitative RT‐PCR on an expanded cohort and by immunohistochemistry. We also revealed significant overexpression of genes involved in the Fanconi anemia (FA) pathway in the C2A subgroup. We then investigated the ability of several described FA inhibitors to block growth of HB cells in vitro and in vivo. We demonstrated that bortezomib, a Food and Drug Administration–approved proteasome inhibitor, strongly impairs the proliferation and survival of HB cell lines in vitro, blocks FA pathway–associated double‐strand DNA repair, and significantly impedes HB growth in vivo. Conclusion: The highly proliferating C2A subtype is characterized by topoisomerase 2‐alpha gene up‐regulation and FA pathway activation, and the HB therapeutic arsenal could include bortezomib for the treatment of patients with the most aggressive tumors. (Hepatology 2018;68:89‐102).
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