Purpose: Clinical variant analysis pipelines likely have poor sensitivity to the effects on splicing from variants beyond 10 to 20 bases of exon-intron boundaries. Here, we demonstrate the value of SpliceAI to inform curation of rare variants previously classified as benign/likely benign (B/LB) under current guidelines.
Methods: Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.
Wilms tumors are commonly associated with predisposition syndromes. Many of these syndromes are associated with specific phenotypic features and are discussed in the related paper from the AACR Pediatric Cancer Working Group. Guidelines for surveillance in this population were published in 2017 but since then several studies have identified new genes with recurrent pathogenic variants associated with increased risk for Wilms tumor development.
View Article and Find Full Text PDFBackground: Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk.
View Article and Find Full Text PDFGermline pathogenic variants in cancer susceptibility genes are identified in up to 18% of all children with cancer. Because pediatric cancer predisposition syndromes (CPS) themselves are rare and underrecognized, there are limited data to guide the diagnosis and management of affected children and at-risk relatives. Furthermore, the care of affected children requires distinct considerations given the early onset of cancers, lifelong risks of additional cancers, and potential late effects of therapy.
View Article and Find Full Text PDFBackground: Patients with chiasmatic-hypothalamic low-grade glioma (CHLGG) have frequent MRIs with gadolinium-based contrast agents (GBCA) for disease monitoring. Cumulative gadolinium deposition in the brains of children is a potential concern. The purpose of this study is to evaluate whether MRI with GBCA is necessary for determining radiographic tumor progression in children with CHLGG.
View Article and Find Full Text PDFGermline PTEN (phosphatase and tensin homolog) mutations lead to inappropriate cell survival and growth, and a predisposition to multiple cancers. Some patients also have vascular anomalies (VAs), and it is unclear whether these patients have different phenotypes or oncologic risks. We conducted a two-institution retrospective cohort study to better understand the phenotypes of children and young adults with PTEN mutations, and to compare individuals with VA to those without.
View Article and Find Full Text PDFCold Spring Harb Mol Case Stud
October 2019
Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline p.
View Article and Find Full Text PDFIntroduction: Methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) has been identified as a potential prognostic biomarker of outcomes in various cancers. We evaluated the prognostic value of blood-derived mdNLR within a retrospective cohort of pediatric medulloblastoma patients.
Materials And Methods: DNA methylation was measured in archival peripheral blood samples collected on 56 pediatric medulloblastoma patients.
Curr Opin Pediatr
February 2019
Purpose Of Review: A significant proportion of pediatric cancer occurs in children with hereditary cancer predisposition syndromes. Their survival may be significantly improved and/or late effects diminished through screening for their greatly elevated cancer risks. Here, an overview of new developments in the field of pediatric cancer surveillance is provided.
View Article and Find Full Text PDFTher Adv Endocrinol Metab
September 2018
Individuals with PTEN Hamartoma Tumor Syndrome (PHTS) are at greatly increased risk for developing well-differentiated thyroid cancer. Specific circumstances in which total thyroidectomies should be considered have not been defined. A 14-year-old macrocephalic female with history of developmental delay and lipoma over her left flank presented with neck swelling and was found have multinodular goiter and auto-immune thyroiditis.
View Article and Find Full Text PDFImportance: Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in surveillance of this high-risk population.
Objective: To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline.
Children and adolescents who present with neuroendocrine tumors are at extremely high likelihood of having an underlying germline predisposition for the multiple endocrine neoplasia (MEN) syndromes, including MEN1, MEN2A and MEN2B, MEN4, and hyperparathyroid-jaw tumor (HPT-JT) syndromes. Each of these autosomal dominant syndromes results from a specific germline mutation in unique genes: MEN1 is due to pathogenic variants (11q13), MEN2A and MEN2B are due to pathogenic variants (10q11.21), MEN4 is due to pathogenic variants (12p13.
View Article and Find Full Text PDFhamartoma tumor syndrome (PHTS), syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma.
View Article and Find Full Text PDFVon Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand.
View Article and Find Full Text PDFBackground: Ototoxicity is a common adverse side effect of platinum chemotherapy and cranial radiation therapy; however, individual susceptibility is highly variable. Therefore, our objective was to conduct an epigenome-wide association study to identify differentially methylated cytosine-phosphate-guanine (CpG) sites associated with ototoxicity susceptibility among cisplatin-treated pediatric patients with embryonal tumors.
Methods: Samples were collected for a discovery cohort (n = 62) and a replication cohort (n = 18) of medulloblastoma and primitive neuroectodermal tumor patients.
Aim: Medulloblastoma is the most frequent malignant pediatric brain tumor. While survival rates have improved due to multimodal treatment including cisplatin-based chemotherapy, there are few prognostic factors for adverse treatment outcomes. Notably, genes involved in the nucleotide excision repair pathway, including ERCC2, have been implicated in cisplatin sensitivity in other cancers.
View Article and Find Full Text PDFGerm-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour.
View Article and Find Full Text PDFIkappaBalpha serves as a central anchoring molecule in the sequestration of NF-kappaB transcription factor in the cytoplasm. Ubiquitination-mediated IkappaBalpha degradation immediately precedes and is required for NF-kappaB nuclear translocation and activation. However, the precise mechanism for the deubiquitination of IkappaBalpha is still not fully understood.
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