TRIM28 inactivation in epithelial nephroblastoma is frequent and often associated with predisposing TRIM28 germline variants

Wilms tumors (WTs) are histologically diverse childhood cancers with variable contributions of blastema, stroma, and epithelia. A variety of cancer genes operate in WTs, including the tripartite-motif-containing-28 gene (TRIM28). Case reports and small case series suggest that TRIM28 mutations are associated with epithelial morphology and WT predisposition. Here, we systematically investigated the prevalence of TRIM28 inactivation and predisposing mutations in a cohort of 126 WTs with >2/3 epithelial cells, spanning 20 years of biobanking in the German SIOP93-01/GPOH and SIOP2001/GPOH studies. Overall, 44.4% (56/126) cases exhibited loss of TRIM28 by immunohistochemical staining. Of these, 48 could be further analyzed molecularly, revealing TRIM28 sequence variants in each case – either homozygous (~2/3) or heterozygous with epigenetic silencing of the second allele (~1/3). The majority (80%) of the mutations resulted in premature stops and frameshifts. In addition, we detected missense mutations and small deletions predicted to destabilize the protein through interference with folding of key structural elements such as the zinc-binding clusters of the RING, B-box-2, and PHD domains or the central coiled-coil region. TRIM28-mutant tumors otherwise lacked WT-typical IGF2 alterations or driver events, except for rare TP53 progression events that occurred with expected frequency. Expression profiling identified TRIM28-mutant tumors as a homogeneous subset of epithelial WTs that mostly present with stage I disease. There was a high prevalence of perilobar nephrogenic rests, putative precursor lesions, that carried the same biallelic TRIM28 alterations in 7/7 cases tested. Importantly, 46% of the TRIM28 mutations were present in blood cells or normal kidney tissue, suggesting germline events or somatic mosaicism, partly supported by family history. Given the high prevalence of predisposing variants in TRIM28-driven WT, we suggest that immunohistochemical testing of TRIM28 be integrated into diagnostic practice as the management of WT in predisposed children differs from that with sporadic tumors. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Characteristics and outcomes of neonatal SARS-CoV-2 infection in the UK: a prospective national cohort study using active surveillance.

BACKGROUND: Babies differ from older children with regard to their exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, data describing the effect of SARS-CoV-2 in this group are scarce, and guidance is variable. We aimed to describe the incidence, characteristics, transmission, and outcomes of SARS-CoV-2 infection in neonates who received inpatient hospital care in the UK. METHODS: We carried out a prospective UK population-based cohort study of babies with confirmed SARS-CoV-2 infection in the first 28 days of life who received inpatient care between March 1 and April 30, 2020. Infected babies were identified through active national surveillance via the British Paediatric Surveillance Unit, with linkage to national testing, paediatric intensive care audit, and obstetric surveillance data. Outcomes included incidence (per 10 000 livebirths) of confirmed SARS-CoV-2 infection and severe disease, proportions of babies with suspected vertically and nosocomially acquired infection, and clinical outcomes. FINDINGS: We identified 66 babies with confirmed SARS-CoV-2 infection (incidence 5·6 [95% CI 4·3-7·1] per 10 000 livebirths), of whom 28 (42%) had severe neonatal SARS-CoV-2 infection (incidence 2·4 [1·6-3·4] per 10 000 livebirths). 16 (24%) of these babies were born preterm. 36 (55%) babies were from white ethnic groups (SARS-CoV-2 infection incidence 4·6 [3·2-6·4] per 10 000 livebirths), 14 (21%) were from Asian ethnic groups (15·2 [8·3-25·5] per 10 000 livebirths), eight (12%) were from Black ethnic groups (18·0 [7·8-35·5] per 10 000 livebirths), and seven (11%) were from mixed or other ethnic groups (5·6 [2·2-11·5] per 10 000 livebirths). 17 (26%) babies with confirmed infection were born to mothers with known perinatal SARS-CoV-2 infection, two (3%) were considered to have possible vertically acquired infection (SARS-CoV-2-positive sample within 12 h of birth where the mother was also positive). Eight (12%) babies had suspected nosocomially acquired infection. As of July 28, 2020, 58 (88%) babies had been discharged home, seven (11%) were still admitted, and one (2%) had died of a cause unrelated to SARS-CoV-2 infection. INTERPRETATION: Neonatal SARS-CoV-2 infection is uncommon in babies admitted to hospital. Infection with neonatal admission following birth to a mother with perinatal SARS-CoV-2 infection was unlikely, and possible vertical transmission rare, supporting international guidance to avoid separation of mother and baby. The high proportion of babies from Black, Asian, or minority ethnic groups requires investigation. FUNDING: UK National Institute for Health Research Policy Research Programme

The varied spectrum of nephroblastomatosis, nephrogenic rests, and Wilms tumors: Review of current definitions and challenges of the field.

The diagnosis of multiple or diffuse renal lesions in a child is challenging by imaging and/or pathology. Optimal management requires distinguishing benign lesions such as nephrogenic rests from cancerous lesions such as Wilms tumor, but this is often difficult or impossible. This difficulty is compounded by the overlapping nature of our current radiologic and pathologic definitions of lesions along the spectrum of nephrogenic rests/nephroblastomatosis. We provide a review of these issues, as a collaborative effort between the Children's Oncology Group Renal Tumor Committee and International Society of Pediatric Oncology Renal Tumor Study Group. Our aim is to discuss current challenges in diagnosis and management of these renal lesions, encouraging future work toward consensus definitions for research and patient care

Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK)

Introduction: Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework. Methods: We evaluated 100 patients recruited within EU-RHAB (2009-2018). Tumours and matching blood samples were examined for SMARCB1 mutations by sequencing and cytogenetics. Results: A total of 70 patients presented with extracranial, extrarenal tumours (eMRT) and 30 with renal rhabdoid tumours (RTK). Nine patients demonstrated synchronous tumours. Distant metastases at diagnosis (M+) were present in 35% (35/100), localised disease (M0) with (LN+) and without (LN-) loco-regional lymph node involvement in 65% (65/100). SMARCB1 germline mutations (GLM) were detected in 21% (17/81 evaluable) of patients. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.8 +/- 5.4% and 35.2 +/- 5.1%, respectively. On univariate analyses, age at diagnosis (>= 12 months), M0-stage, absence of synchronous tumours, absence of a GLM, gross total resection (GTR), radiotherapy and achieving a CR were significantly associated with favourable outcomes. In an adjusted multivariate model presence of a GLM, M+ and lack of a GTR were the strongest significant negative predictors of outcome. Conclusions: We suggest to stratify patients with localised disease (M0), GTR+ and without proof of a GLM (5-year OS 72.2 +/- 9.9%) as 'standard risk'. Patients presenting with one of the features M+ and/or GTR - and/ or GLM+ belong to a high risk group (5-year, OS 32.5 +/- 6.2%). These patients need novel therapeutic strategies such as combinations of targeted agents with conventional chemotherapy or novel experimental approaches ideally within international phase I/II trials. (C) 2020 Elsevier Ltd. All rights reserved

Hallmark discoveries in the biology of Wilms tumour

The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the ‘two-hit’ model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics — from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions