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The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis.
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Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a rare condition associated with vascular anomalies and increased tumor risk. Sirolimus, an mTOR inhibitor used for managing vascular anomalies is underexplored in PHTS. A single-institution retrospective review of children with PHTS and vascular anomalies treated with sirolimus identified seven patients. Median age at sirolimus initiation was 10 years. After a median 2.5-year follow-up, six of seven patients (86%) showed significant clinical improvement. No significant adverse effects were observed, except mild buccal ulcers and acne. This study supports sirolimus as an effective and safe treatment for vascular anomalies in a small group of children with PHTS.
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INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.
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Neoplasias Renais , Tumor de Wilms , Humanos , Tumor de Wilms/patologia , Tumor de Wilms/mortalidade , Tumor de Wilms/terapia , Tumor de Wilms/cirurgia , Masculino , Feminino , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Neoplasias Renais/terapia , Neoplasias Renais/cirurgia , Pré-Escolar , Lactente , Anaplasia/patologia , Criança , Prognóstico , Taxa de Sobrevida , Seguimentos , NefrectomiaRESUMO
Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research.
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Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Metilação de DNA , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Mutação , Complexo Repressor Polycomb 2/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Mosaicismo , Mutação de Sentido Incorreto/genética , Proteínas de Neoplasias , Reprodutibilidade dos Testes , Fatores de Transcrição , Adulto JovemRESUMO
Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Genes do Tumor de Wilms , Síndrome , Tumor de Wilms/patologia , Neoplasias Renais/patologia , Genótipo , Suscetibilidade a DoençasRESUMO
PURPOSE: We compare differences in long-term kidney function between patients undergoing either radical nephrectomy (RN) or nephron-sparing surgery (NSS) in unilateral and bilateral Wilms tumor (WT), respectively. MATERIALS AND METHODS: A systematic search was performed in September 2020. Comparative studies were evaluated according to Cochrane collaboration recommendations. Assessed long-term (>1-year postoperative) outcomes included chronic kidney disease, hypertension and glomerular filtration rate, among others. Odds ratio and mean difference with 95% confidence interval were extrapolated from available data for quantitative synthesis. Random-effects meta-analysis and meta-regression were performed according to study design and techniques. The systematic review was prospectively registered on PROSPERO (CRD42020205378). RESULTS: A total of 23 studies describing 293 cases of unilateral WT and 386 cases of bilateral WT were included in the qualitative synthesis. Overall effect estimates demonstrate that patients undergoing RN have significantly increased odds of developing abnormal kidney function (OR 4.29, 95% CI 1.02, 18.00) and lower estimated glomerular filtration rate at long-term followup (mean difference -8.99, 95% CI -16.40, -1.58) compared to those undergoing NSS. In bilateral WT, patients undergoing RN with contralateral NSS have higher odds of developing abnormal kidney function (OR 3.82, 95% CI 1.76, 8.33) and hypertension (OR 5.81, 95% CI 1.31, 25.68) compared to bilateral NSS. CONCLUSIONS: Current evidence is low quality but suggests that NSS for unilateral and bilateral WT may be associated with better kidney function or blood pressure at late followup. Further research to investigate sources of heterogeneity is recommended.
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Neoplasias Renais/cirurgia , Nefrectomia/métodos , Tumor de Wilms/cirurgia , Humanos , Testes de Função Renal , Néfrons/cirurgiaRESUMO
BACKGROUND: Although cure rates for Wilms tumours (WT) are high, many patients receive therapy with attendant long-term complications. Our goal was to stratify WT using genome-wide analyses to identify candidate molecular features for patients who would benefit from a reduction in therapy. METHODS: We generated DNA methylation and exome sequencing data on WT-kidney pairs (n = 57) and unpaired tumours (n = 27) collected either at our centre or by the Children's Oncology Group. Samples were divided into a discovery set (n = 32) and validation set (n = 52). RESULTS: Analysis of DNA methylation revealed two subgroups of WT with distinct features. Subgroup A has a similar DNA methylation profile to mature kidney, while Subgroup B has genome-wide dysregulation of DNA methylation. The rate of non-synonymous missense mutations and segmental chromosomal aberrations was higher in Subgroup B tumours, suggesting that this group has genome instability related to its epigenetic state. Subgroup A had a higher proportion of cases of bilateral disease. Tumours with high-risk histology or from patients who relapsed were only found in Subgroup B. CONCLUSION: We have identified subgroup-specific molecular events that could inform future work supporting more targeted therapeutic approaches and patient stratification. We propose a novel developmental tumour model based on these findings.
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Neoplasias Renais/genética , Tumor de Wilms/genética , Criança , Aberrações Cromossômicas , Metilação de DNA/genética , Feminino , Perfilação da Expressão Gênica/métodos , Genes do Tumor de Wilms , Humanos , Neoplasias Renais/classificação , Masculino , Mutação , Sequenciamento do Exoma , Tumor de Wilms/classificaçãoRESUMO
OBJECTIVE: To present our proof of concept with semi-automatic image recognition/segmentation technology for calculation of tumour/parenchyma volume. METHODS: We reviewed Wilms' tumours (WTs) between 2000 and 2018, capturing computed tomography images at baseline, after neoadjuvant chemotherapy (NaC) and postoperatively. Images were uploaded into MATLAB-3-D volumetric image processing software. The program was trained by two clinicians who supervised the demarcation of tumour and parenchyma, followed by automatic recognition and delineation of tumour margins on serial imaging, and differentiation from uninvolved renal parenchyma. Volume was automatically calculated for both. RESULTS: During the study period, 98 patients were identified. Of these, based on image quality and availability, 32 (38 affected moieties) were selected. Most patients (65%) were girls, diagnosed at age 50 ± 37 months of age. NaC was employed in 64% of patients. Surgical management included 27 radical and 11 partial nephrectomies. Automated volume assessment demonstrated objective response to NaC for unilateral and bilateral tumours (68 ± 20% and 53 ± 39%, respectively), as well as preservation on uninvolved parenchyma with partial nephrectomy (70 ± 46 cm3 at presentation to 57 ± 41 cm3 post-surgery). CONCLUSION: Volumetric analysis is feasible and allows objective assessment of tumour and parenchyma volume in response to chemotherapy and surgery. Our data show changes after therapy that may be otherwise difficult to quantify. Use of such technology may improve surgical planning and quantification of response to treatment, as well as serving as a tool to predict renal reserve and long-term changes in renal function.
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Algoritmos , Antineoplásicos/uso terapêutico , Imageamento Tridimensional/métodos , Neoplasias Renais/diagnóstico , Nefrectomia/métodos , Tomografia Computadorizada por Raios X/métodos , Tumor de Wilms/diagnóstico , Adolescente , Quimioterapia Adjuvante , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Lactente , Recém-Nascido , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Masculino , Terapia Neoadjuvante , Tamanho do Órgão , Estudos Retrospectivos , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/cirurgiaRESUMO
Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10(-8)). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
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Neoplasias Encefálicas/genética , Carcinoma/genética , Neoplasias do Plexo Corióideo/genética , Glioma/genética , Tumores Neuroectodérmicos Primitivos/genética , Telômero , Proteína Supressora de Tumor p53/genética , Adolescente , Neoplasias Encefálicas/fisiopatologia , Carcinoma/fisiopatologia , Neoplasias do Plexo Corióideo/fisiopatologia , Estudos de Coortes , DNA Helicases/genética , Glioma/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Mutação , Gradação de Tumores , Tumores Neuroectodérmicos Primitivos/fisiopatologia , Proteínas Nucleares/genética , Fenótipo , Prognóstico , Telômero/metabolismo , Proteína Nuclear Ligada ao XRESUMO
Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.
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Neoplasias Encefálicas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Síndromes Neoplásicas Hereditárias , Humanos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/diagnóstico , Criança , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/epidemiologia , Testes Genéticos , Guias de Prática Clínica como AssuntoRESUMO
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.
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Neoplasias Renais , Tumor de Wilms , Humanos , Neoplasias Renais/terapia , Recidiva Local de Neoplasia , Tumor de Wilms/terapia , Biomarcadores , BiologiaRESUMO
BACKGROUND: Bilateral Wilms tumor (BWT) is a rare entity. The goal of this study is to report outcomes (overall and event-free survival, OS/EFS) of BWT in a large cohort representative of the Canadian population since 2000. We focused on the occurrence of late events (relapse or death beyond 18 months), as well as outcomes of patients treated following the only protocol specifically designed for BWT to date, AREN0534, compared to patients treated following other therapeutic schemes. METHODS: Data was obtained for patients diagnosed with BWT between 2001 and 2018 from the Cancer in Young People in Canada (CYP-C) database. Demographics, treatment protocols, and dates for events were collected. Specifically, we examined outcomes of patients treated according to the Children's Oncology Group (COG) protocol AREN0534 since 2009. Survival analysis was performed. RESULTS: 57/816 (7%) of patients with Wilms tumor had BWT during the study period. Median age at diagnosis was 2.74 years (IQR 1.37-4.48) and 35 (64%) were female; 8/57 (15%) had metastatic disease. After a median follow-up of 4.8 years (IQR 2.8-5.7 years, range 0.2-18 years), OS and EFS were 86% (CI 73-93%) and 80% (CI 66-89%), respectively. Less than 5 events were recorded after 18 months from diagnosis. Since 2009, patients treated according to the AREN0534 protocol had a statistically significant higher OS compared to patients treated with other protocols. CONCLUSIONS: In this large Canadian cohort of patients with BWT, OS and EFS compared favorably to the published literature. Late events were rare. Patients treated according to a disease-specific protocol (AREN0534) had improved overall survival. TYPE OF STUDY: Original article. LEVEL OF EVIDENCE: Level IV.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Feminino , Lactente , Adolescente , Masculino , Neoplasias Renais/epidemiologia , Neoplasias Renais/terapia , Neoplasias Renais/diagnóstico , Nefrectomia/métodos , Recidiva Local de Neoplasia/patologia , Canadá/epidemiologia , Tumor de Wilms/epidemiologia , Tumor de Wilms/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de NeoplasiasRESUMO
OBJECTIVE: To determine the patient characteristics and role of nephron-sparing surgery (NSS) in the treatment of children and young adults with renal cell carcinoma (RCC). METHODS: A systematic search of Embase, MEDLINE, and Scopus databases was conducted in December 2021 according to Cochrane collaboration recommendations. All included manuscripts were assessed for patient characteristics and all reported outcomes for patients undergoing partial nephrectomy (PN), and radical nephrectomy (RN) outcomes were abstracted as a comparison group. Primary outcomes included surgical outcomes, overall survival, kidney outcomes. Outcomes were pooled with weighted mean and ranges. Meta-analysis was not performed given study quality. This systematic review was prospectively registered on PROSPERO (CRD42022300261). RESULTS: We found a total of 16 studies describing 119 and 559 unique patients undergoing PN and RN, respectively, with a mean age of 12.2 years and mean follow-up of 59.1 months. The mean tumor size for patients undergoing PN was 3.5 cm. Of the 113 patients undergoing PN with available data, 109 were alive at follow-up (98%). No studies reported long-term kidney outcomes, and four studies reported surgical outcomes. All studies had at least moderate risk of bias. CONCLUSIONS: The use of NSS in children and young adults with RCC is feasible in selected patients. However, small sample sizes, confounding, and low study quality limit clinical recommendation on NSS in this population. There are significant opportunities for future research on the use of NSS in RCC, especially with systematic reporting of oncological, kidney, and surgical outcomes.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Criança , Adulto Jovem , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Nefrectomia/efeitos adversos , Rim/patologia , Néfrons/cirurgia , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer-predisposition disorder. Approximately 70% of individuals who fit the clinical definition of LFS harbor a pathogenic germline variant in the TP53 tumor suppressor gene. However, the remaining 30% of patients lack a TP53 variant and even among variant TP53 carriers, approximately 20% remain cancer-free. Understanding the variable cancer penetrance and phenotypic variability in LFS is critical to developing rational approaches to accurate, early tumor detection and risk-reduction strategies. We leveraged family-based whole-genome sequencing and DNA methylation to evaluate the germline genomes of a large, multi-institutional cohort of patients with LFS (n = 396) with variant (n = 374) or wildtype TP53 (n = 22). We identified alternative cancer-associated genetic aberrations in 8/14 wildtype TP53 carriers who developed cancer. Among variant TP53 carriers, 19/49 who developed cancer harbored a pathogenic variant in another cancer gene. Modifier variants in the WNT signaling pathway were associated with decreased cancer incidence. Furthermore, we leveraged the noncoding genome and methylome to identify inherited epimutations in genes including ASXL1, ETV6, and LEF1 that confer increased cancer risk. Using these epimutations, we built a machine learning model that can predict cancer risk in patients with LFS with an area under the receiver operator characteristic curve (AUROC) of 0.725 (0.633-0.810). Significance: Our study clarifies the genomic basis for the phenotypic variability in LFS and highlights the immense benefits of expanding genetic and epigenetic testing of patients with LFS beyond TP53. More broadly, it necessitates the dissociation of hereditary cancer syndromes as single gene disorders and emphasizes the importance of understanding these diseases in a holistic manner as opposed to through the lens of a single gene.
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Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Predisposição Genética para Doença/genética , Genes p53 , Mutação em Linhagem Germinativa/genéticaRESUMO
This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group. We found that 25/61 (41%) of patients evaluated harbored pathogenic or likely pathogenic germline variants, with WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA1, BRCA2, and PALB2 being most common. Germline WT1 variants were strongly associated with somatic paternal uniparental disomy encompassing the 11p15.5 and 11p13/WT1 loci and subsequent acquired pathogenic CTNNB1 variants. Somatic coding variants or genome-wide copy number alterations were almost never shared between paired synchronous BWT, suggesting that the acquisition of independent somatic variants leads to tumor formation in the context of germline or early embryonic, post-zygotic initiating events. In contrast, 11p15.5 status (loss of heterozygosity, loss or retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant molecular events for BWT predisposition include pathogenic germline variants or post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (loss of imprinting). This study demonstrates that post-zygotic somatic mosaicism for 11p15.5 hypermethylation/loss of imprinting is the single most common initiating molecular event predisposing to BWT. Evidence of somatic mosaicism for 11p15.5 loss of imprinting was detected in leukocytes of a cohort of BWT patients and long-term survivors, but not in unilateral Wilms tumor patients and long-term survivors or controls, further supporting the hypothesis that post-zygotic 11p15.5 alterations occurred in the mesoderm of patients who go on to develop BWT. Due to the preponderance of BWT patients with demonstrable germline or early embryonic tumor predisposition, BWT exhibits a unique biology when compared to unilateral Wilms tumor and therefore warrants continued refinement of its own treatment-relevant biomarkers which in turn may inform directed treatment strategies in the future.
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Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition.
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Neoplasias Renais , Tumor de Wilms , Criança , Humanos , Tumor de Wilms/genética , Tumor de Wilms/patologia , Genótipo , Metilação de DNA/genética , DNA , Neoplasias Renais/genética , Neoplasias Renais/patologia , Epigênese Genética , Impressão GenômicaRESUMO
We consider 36 planar nets identified by O'Keeffe and Hyde and calculate for each, using the theory of finite Markovian processes, the overall mean walk length n (first passage time) of a reactant diffusing randomly on a finite platelet before being trapped at a reaction center; the results are analyzed in terms of the total number N of lattice sites, the number N(b) of boundary sites, the average valence nu, and the bond orientation function Psi. We establish that crystalline platelets that are members of the same compatible class are characterized by very comparable catalytic efficiencies. The results obtained are also linked to an analysis of the kinetics of docking in postnucleation stages of protein self-assembly and to a recent conjecture on the symmetries of planar nets and the hard disk freezing transition.
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Difusão , Modelos Químicos , Ligas/química , Cristalização , Cinética , Cadeias de Markov , Propriedades de SuperfícieRESUMO
PURPOSE OF REVIEW: Hereditary disorders affecting growth (both overgrowth and growth retardation) are frequently associated with heightened risk of neoplastic disease. This review summarizes the tumor spectra associated with these conditions and identifies disease-specific screening approaches. RECENT FINDINGS: An understanding of the molecular events underlying many of these growth disorders has evolved significantly over the past several years. Recognition of genotype-phenotype associations, in many cases, informs the cancer risk profile. Additionally, accumulating data suggest a benefit of rational presymptomatic surveillance for at-risk individuals, with a reduction in tumor-associated morbidity. Recent clinical practice recommendations have established risk-driven paradigms for tumor surveillance in the context of hereditary tumor predisposition syndromes, including those affecting growth. SUMMARY: Clinicians caring for children with growth disorders should be aware of syndromic associations and the associated cancer risks. Knowledge of tumor spectra and recommended surveillance strategies may facilitate tumor diagnosis at an early stage and reduce morbidity of the disease and associated treatments.
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Desenvolvimento Infantil/fisiologia , Monitorização Fisiológica/métodos , Síndromes Neoplásicas Hereditárias/terapia , Criança , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/fisiopatologia , Neoplasias/terapia , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/fisiopatologia , Fatores de RiscoRESUMO
We examine the conjecture that in a 2D system of hard disks the packing fraction at which the continuous transition from the ordered 2D solid to the hexatic phase occurs, and that at which the very weak first-order or continuous transition from the hexatic to the fluid phase occurs, can be correlated with the packing fractions of patterned networks (tessellations) of disk positions that span the 2D space. We identify three tessellations that have less than close packed density, span 2D space, and have percolated continuity of disk-disk contact. One has a packing fraction of eta = 0.729, very slightly larger than the estimated packing fraction at the ordered solid-to-hexatic transition, eta = 0.723, and the other two have packing fractions of approximately 0.680, slightly smaller than that identified as the upper end of the stability range of the liquid phase, eta = 0.699. The region 0.680 < eta < 0.729 is identified with the hexatic domain. The end points of this region can be placed in correspondence with nets for which the defining unit structures are regular polygons, but not the hexatic domain, in which there are randomly dispersed clusters that need not be regular polygons. The densities at which the percolated tessellations span the 2D space are regarded as special points along the density axis. We suggest that the possibility of forming different symmetry nets with sensibly the same packing fraction is a geometric analogue of a bifurcation condition that divides the configuration space into qualitatively different domains, and that the onset and end of the hexatic region are correlated with such divisions of the configuration space.
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Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children with BWS and loss of methylation at IC2 has been proposed in several recent publications. We report here three children with BWS reported to have loss of methylation at IC2 on clinical testing who developed Wilms tumour or precursor lesions. Using multiple molecular approaches and multiple tissues, we reclassified one of these cases to paternal uniparental disomy for chromosome 11p15.5. These cases highlight the current challenges in definitively assigning tumour risk based on molecular classification in BWS. The confirmed cases of loss of methylation at IC2 also suggest that the risk of Wilms tumour in this population is not as low as previously thought. Therefore, we recommend that for now, all children with a clinical or molecular diagnosis of BWS be screened for Wilms tumour by abdominal ultrasonography until the age of eight years regardless of the molecular classification.