Germline Mutations in Predisposition Genes in Pediatric Cancer

Bardai, Abdenasser; Overwater, Eline; Aalfs, Cora M.

doi:10.1056/nejmc1600338

Cited by 16 publications

(13 citation statements)

References 38 publications

(39 reference statements)

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“…Somatic mutations occurring in protein-coding regions of signature genes were manually reviewed and reported. Germline mutations were annotated with Medal Ceremony as previously described [ 51 ]. Additional filters were applied to keep rare and potentially deleterious germline variants: (1) coverage is no less than 10×; (2) variant allele fraction (VAF) of the variant is no less than 0.2; (3) the max population frequency is less than 0.001 in ExAC; (4) non-synonymous variants including missense, nonsense, in-frame insertion/deletion (indel), frameshift indel and splice mutations; and (5) for missense mutation, REVEL score greater than 0.5 or missing REVEL scores.…”

Section: Methodsmentioning

confidence: 99%

“…Additional filters were applied to keep rare and potentially deleterious germline variants: (1) coverage is no less than 10×; (2) variant allele fraction (VAF) of the variant is no less than 0.2; (3) the max population frequency is less than 0.001 in ExAC; (4) non-synonymous variants including missense, nonsense, in-frame insertion/deletion (indel), frameshift indel and splice mutations; and (5) for missense mutation, REVEL score greater than 0.5 or missing REVEL scores. For tumor samples lacking paired germline samples, the variants were called by Bambino [ 9 ] and annotated by Medal Ceremony as Gold, Silver, Bronze, or Unknown [ 51 ]. We retained all the Gold variants.…”

Section: Methodsmentioning

confidence: 99%

Section: Whole Genome and Whole Exome Sequencing Analysismentioning

confidence: 99%

See 2 more Smart Citations

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Smith

Mercer

et al. 2020

Acta Neuropathol

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Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Whole Genome and Whole Exome Sequencing Analysismentioning

confidence: 99%

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Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Smith

Mercer

et al. 2020

Acta Neuropathol

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“…3b ). Several germline mutations have been shown to predispose to pediatric sarcoma development, including mutations in p53, PMS2, RET, RB1, and PALB2 83 .…”

Section: Modeling Sarcoma Developmentmentioning

confidence: 99%

Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies

Navarro

Susanto

Falk

et al. 2018

Cell Death Discovery

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In vitro modeling of complex diseases is now a possibility with the use of patient-derived induced pluripotent stem (iPS) cells. Their stem cell properties, including self-renewal and their potential to virtually differentiate into any cell type, emphasize their importance as a translational tool for modeling disorders that so far have been limited by the unavailability of primary cell lines, animal models, or inaccessible human materials. Around 100 genes with germline mutations have been described to be responsible for cancer predisposition. Familial cancers are usually diagnosed earlier in life since these patients already carry the first transforming hit. Deriving iPS cells from patients suffering from familial cancers provides a valuable tool for understanding the mechanisms underlying pediatric cancer onset and progression since they require less mutation recurrence than adult cancers to develop. At the same time, some familial mutations are found in sporadic cases and are a valuable prognostic tool. Patient-derived iPS cells from germline malignancies can also create new tools in developing specific drugs with more personalized-therapy strategies.

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“…There are a number of studies that describe an association between early onset cancer and DNMs in father's gametes [ 103 ]. Recently a comprehensive study analyzed numerous genes known to be recurrently mutated in cancer, looking for evidence of germ line mosaicism [ 104 ]. Interestingly, they found that 8.5% of the patients analyzed harbored germ line mutations in genes related to cancer predisposition.…”

Section: Neuropsychiatric Disorders Congenital Heart Disease and Camentioning

confidence: 99%

Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention

Yamada

Chiara

Seandel

2016

Stem Cells and Development

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Spermatogonial stem cells (SSCs) propagate mammalian spermatogenesis throughout male reproductive life by continuously self-renewing and differentiating, ultimately, into sperm. SSCs can be cultured for long periods and restore spermatogenesis upon transplantation back into the native microenvironment in vivo. Conventionally, SSC research has been focused mainly on male infertility and, to a lesser extent, on cell reprogramming. With the advent of genome-wide sequencing technology, however, human studies have uncovered a wide range of pathogenic alleles that arise in the male germ line. A subset of de novo point mutations was shown to originate in SSCs and cause congenital disorders in children. This review describes both monogenic diseases (eg, Apert syndrome) and complex disorders that are either known or suspected to be driven by mutations in SSCs. We propose that SSC culture is a suitable model for studying the origin and mechanisms of these diseases. Lastly, we discuss strategies for future clinical implementation of SSC-based technology, from detecting mutation burden by sperm screening to gene correction in vitro.

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Germline Mutations in Predisposition Genes in Pediatric Cancer

Cited by 16 publications

References 38 publications

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Patient-derived orthotopic xenografts of pediatric brain tumors: a St. Jude resource

Modeling cancer using patient-derived induced pluripotent stem cells to understand development of childhood malignancies

Spermatogonial Stem Cells: Implications for Genetic Disorders and Prevention

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