Publications by authors named "Jacquelyn Reuther"

Purpose: To evaluate the relative diagnostic yield of clinical germline genomic tests in a diverse pediatric cancer population.

Patients And Methods: The KidsCanSeq study enrolled pediatric cancer patients across six sites in Texas. Germline analysis included both exome sequencing and a therapy-focused pediatric cancer gene panel.

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Recognition of patients with multiple diagnoses, and the unique challenges they pose to clinicians and laboratorians, is increasing rapidly as genome-wide genetic testing grows in prevalence. We describe a unique patient with dual diagnoses of PDCD10-related cerebral cavernous malformations and ETV6-related thrombocytopenia with associated neutropenia. She presented with brain abscesses as an infant, which is highly atypical for these disorders in isolation.

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Diagnosing, selecting therapy for, and monitoring cancer in patients using a minimally invasive blood test represents a significant advance in precision medicine. Wide variability exists in how circulating tumor DNA (ctDNA) assays are developed, validated, and reported in the literature, which hinders clinical adoption and may negatively impact patient care. Standardization is needed for factors affecting ctDNA assay performance and reporting, including pre-analytical variables, analytical considerations, and elements of laboratory assay reporting.

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Background: Highly sensitive molecular assays have been developed to detect plasma-based circulating tumor DNA (ctDNA), and emerging evidence suggests their clinical utility for monitoring minimal residual disease and recurrent disease, providing prognostic information, and monitoring therapy responses in patients with solid tumors. The Invitae Personalized Cancer Monitoring assay uses a patient-specific, tumor-informed variant signature identified through whole exome sequencing to detect ctDNA in peripheral blood of patients with solid tumors.

Methods: The assay's tumor whole exome sequencing and ctDNA detection components were analytically validated using 250 unique human specimens and nine commercial reference samples that generated 1349 whole exome sequencing and cell-free DNA (cfDNA)-derived libraries.

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Article Synopsis
  • The study explored the use of circulating tumor DNA (ctDNA) as a "liquid biopsy" for children with solid tumors, focusing on its feasibility and clinical usefulness in real-time monitoring of their conditions.
  • Out of 240 patients, plasma samples from 217 were analyzed, achieving a high success rate of 99.5% for extracting and quantifying cell-free DNA.
  • The ctDNA analysis showed better mutation detection rates in non-CNS solid tumors and metastatic cases, suggesting its potential for tracking cancer progression in young patients.
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Background: The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD).

Procedure: We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies.

Results: There were six of 773 (0.

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Somatic copy number alterations (SCNAs) in tumors are clinically significant diagnostic, prognostic, and predictive biomarkers. SCNA detection from targeted next-generation sequencing panels is increasingly common in clinical practice; however, detailed descriptions of optimization and validation of SCNA pipelines for small targeted panels are limited. This study describes the validation and implementation of a tumor-only SCNA pipeline using CNVkit, augmented with custom modules and optimized for clinical implementation by testing reference materials and clinical tumor samples with different classes of copy number variation (CNV; amplification, single copy loss, and biallelic loss).

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Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs).

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Article Synopsis
  • The MYOD1 p.L122R mutation was found in aggressive embryonal rhabdomyosarcomas and other types of rhabdomyosarcomas, highlighting its significance in cancer research.
  • A study at Texas Children's Hospital identified this mutation in six tumors and revealed multiple genomic alterations, with a high rate of targetable mutations in the patients, particularly in the PI3K-AKT pathway.
  • The research also showed that MYOD1-mutant tumors had distinct histopathological features and patients with these tumors had poor outcomes, suggesting a need for targeted therapies and better understanding of the genetic landscape in pediatric sarcomas.
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Background: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy.

Methods: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively.

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Adult granulosa cell tumor (AGCT) and sex cord tumor with annular tubules (SCTAT) are distinct sex cord stromal tumors with different molecular signatures. We present a unique case of an incidental ovarian tumor with mixed AGCT and SCTAT morphologic patterns. Due to the unusual co-occurrence, molecular testing was separately performed on both components.

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Background: Lipofibromatosis-like neural tumors (LPF-NT) are a newly identified class of rare mesenchymal neoplasms. Current standard of care therapy is surgical resection alone; there are no chemotherapies or molecular targeted therapies that have been shown to be effective in patients who are not surgical candidates due to either tumor bulk or location. Most LPF-NT harbor NTRK fusions, although the therapeutic significance of these fusions has not been previously demonstrated in this malignancy.

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Myeloid sarcoma (MS) is a neoplastic condition composed of immature myeloid cells involving an extramedullary site. We investigated underlying chromosomal and molecular alterations to assess potential molecular markers of prognosis and outcome in this rare pediatric disease. We conducted a retrospective review of clinicopathologic and cytogenetic data from 33 pediatric patients with MS (ages 1 month-18 years) at our institution over a 32 year period (1984-2016).

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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.

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Nodular fasciitis is a self-limited myofibroblastic lesion that can be misdiagnosed as a sarcoma as a result of its rapid growth, cellularity, and sometimes prominent mitotic activity. A recurrent translocation t(17;22) has been identified in nodular fasciitis, fusing the coding region of USP6 to the promoter region of MYH9, and resulting in increased USP6 expression. A subset of cases show USP6 rearrangement without the typical fusion variants by RT-PCR, or any MYH9 rearrangement by FISH.

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Elucidation of the regulatory controls on epithelial plasticity is pivotal not only to better understand the nature of metastasis but also for the design of targeted therapies to prevent the earliest steps in migration and invasion from the primary tumor. This review will highlight the role of the novel TRIM protein DEAR1 (annotated as TRIM62) in the regulation of apical-basal polarity and acinar morphogenesis as well as its function as a chromosome 1p35 tumor suppressor and negative regulator of TGFβ-driven epithelial-mesenchymal transition (EMT). DEAR1 binds to and promotes the ubiquitination of SMAD3, the major effector of TGFβ-mediated EMT, as well as downregulates SMAD3 targets SNAIL1/2, master transcriptional regulators of EMT.

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Unlabelled: Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1(-/-) and Dear1(+/-) mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice.

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