About

Jaclyn A. Biegel, Ph.D., is an Emeritus Professor and Chief of Pediatrics (Human Genetics) at the University of Pennsylvania's Perelman School of Medicine. She is affiliated with The Children's Hospital of Philadelphia. Her research expertise includes cancer cytogenetics, the genetics of pediatric brain tumors, and rhabdoid tumors. Her clinical expertise also encompasses cancer cytogenetics. Dr. Biegel has made significant contributions to the understanding of the molecular and cytogenetic basis of childhood brain tumors and rhabdoid tumors, with numerous publications detailing her work in genomic analysis, mutations, and genetic alterations associated with these cancers.

Research topics

• Biology
• Medicine
• Genetics
• Pathology
• Cancer research

Selected publications

• Low-Pass Whole Genome Sequencing of Cell-Free DNA from Cerebrospinal Fluid: A Focus on Pediatric Central Nervous System Tumors

  Clinical Chemistry · 2025-01-01 · 5 citations

  review

  BACKGROUND: Cell-free DNA (cfDNA) technology has allowed for cerebrospinal fluid (CSF), a previously underutilized biofluid, to be analyzed in new ways. The interrogation of CSF-derived cfDNA is giving rise to novel molecular insights, particularly in pediatric central nervous system (CNS) tumors, where invasive tumor tissue acquisition may be challenging. Contemporary disease monitoring is currently restricted to radiographic surveillance by magnetic resonance imaging and CSF cytology to directly detect abnormal cells and cell clusters. Alternatively, cfDNA is often present in the CSF from pediatric patients with both malignant and nonmalignant CNS tumors and can be accessed by minimally invasive lumbar puncture and other CSF-liberating procedures, offering a promising alternative for longitudinal molecular disease analysis and surveillance. CONTENT: This review explores the use of low-pass whole genome sequencing (LP-WGS) to analyze cfDNA from the CSF of pediatric patients with CNS tumors. This platform is uniquely poised for the detection of tumors harboring copy number variants, which are prevalent in this population. The utility and sensitivity of LP-WGS as a clinical tool is explored and discussed in the context of alternative CSF liquid biopsy interrogation modalities, including nanopore sequencing and methylation array. SUMMARY: Analysis of CSF-derived cfDNA by LP-WGS has broad diagnostic, prognostic, and clinical implications for pediatric patients with CNS tumors. Careful interpretation of LP-WGS results may aid in therapeutic targeting of pediatric CNS tumors and may provide insight into tumor heterogeneity and evolution over time, without the need for invasive and potentially risky tissue sampling.

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• SMARCB1 missense mutants disrupt SWI/SNF complex stability and remodeling activity

  Research Square · 2025-03-26 · 1 citations

  preprintOpen access
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• Distinct Mitochondrial DNA Deletion Profiles in Pediatric B- and T-ALL During Diagnosis, Remission, and Relapse

  International Journal of Molecular Sciences · 2025-07-23 · 1 citations

  articleOpen access

  Mitochondria are critical for cellular energy, and while large deletions in their genome (mtDNA) are linked to primary mitochondrial diseases, their significance in cancer is less understood. Given cancer's metabolic nature, investigating mtDNA deletions in tumors at various stages could provide insights into disease origins and treatment responses. In this study, we analyzed 148 bone marrow samples from 129 pediatric patients with B-cell (B-ALL) and T-cell (T-ALL) acute lymphoblastic leukemia at diagnosis, remission, and relapse using long-range PCR, next-generation sequencing, and the Splice-Break2 pipeline. Both T-ALL and B-ALL exhibited significantly more mtDNA deletions than did the controls, with T-ALL showing a ~100-fold increase and B-ALL a ~15-fold increase. The T-ALL samples also exhibited larger deletions (median size > 2000 bp) and greater heterogeneity, suggesting increased mitochondrial instability. Clustering analysis revealed distinct deletion profiles between ALL subtypes and across disease stages. Notably, large clonal deletions were detected in some B-ALL remission samples, including one affecting up to 88% of mtDNA molecules, which points toward treatment-driven selection or toxicity. A multivariate analysis confirmed that disease type, timepoint, and WHO subtype significantly influenced mtDNA deletion metrics, while age and gender did not. These findings suggest that mtDNA deletion profiling could serve as a biomarker for pediatric ALL and may indicate mitochondrial toxicity contributing to late effects in survivors.

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• Germline Cancer Predisposition Results From the National Cancer Institute—Children's Oncology Group Pediatric MATCH Trial

  JCO Precision Oncology · 2025-10-01 · 3 citations

  articleOpen access

  PURPOSE Precision oncology trials have generally focused on tumor testing to identify actionable alterations. The National Cancer Institute—Children's Oncology Group Pediatric MATCH trial incorporated return of germline results to assess feasibility of reporting in a cooperative group setting and characterize germline cancer predisposition in patients with refractory cancers. PATIENTS AND METHODS Tumor and blood DNA from patients 1-21 years of age with treatment-refractory solid tumors, non-Hodgkin lymphomas, or histiocytic disorders underwent cancer gene panel sequencing. Clinical germline reports returned to 151 study sites included pathogenic/likely pathogenic (P/LP) germline variants found in 38 cancer predisposition genes (CPGs). European Society of Medical Oncology (ESMO) recommendations for germline follow-up of tumor variants in CPGs were assessed. RESULTS Both tumor and germline reports were completed for 1,167 patients (87.5% of enrolled). A total of 295 tumor reports (25%) included 361 CPG variants of which 70 variants (19.4%) were found in the germline sample. Three additional germline-only CPG variants resulted in 73 (6.3%) of 1,167 germline reports containing variants across 21 CPGs previously associated with pediatric and/or adult cancers. Among frequently mutated CPGs in tumors, concurrent germline findings ranged from 8/32 NF1 (25.0%) and 25/163 TP53 (15.3%) to zero of 27 ALK and 18 PTEN tumor variants. ESMO guidelines recommended clinical follow-up for 110 (30.5%) of 361 tumor CPG variants which included 40 (57.1%) of 70 germline variants. CONCLUSION Coordinated germline and tumor panel testing was feasible and revealed P/LP CPG variants in 6.3% of the Pediatric MATCH cohort. Tumor variant fraction, germline association of CPG with tumor type, and adult-oriented guidelines were not predictive of germline status, emphasizing the need for systematic germline follow-up after tumor genomic testing for pediatric patients.

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• The use of aqueous humor cfDNA for low-pass whole genome sequencing as a clinical test to identify intraocular retinoblastoma recurrence

  ScienceBank · 2025-06-03 · 1 citations

  articleOpen access

  Objective: Patients with retinoblastoma (RB) require serial examinations under anesthesia (EUA) to assess for response to treatment and disease recurrence. Monitoring for disease recurrence is complicated in patients with loss of fundoscopic view, such as with vitreous hemorrhage (VH) or cataract. Herein, we report a case of a 13-month-old male diagnosed with sporadic bilateral retinoblastoma, wherein the aqueous humor liquid biopsy was used to detect an occult tumor recurrence after 3.5 years of disease stability. Methodology: Case report. Results: A 13-month-old male diagnosed with sporadic bilateral retinoblastoma, International Intraocular Retinoblastoma Classification (IIRC) Group D1 in the right eye and Group E in the left eye, was initially treated with intravenous chemotherapy, intravitreal chemotherapy, and local consolidation. After 3.5 years of disease stability, the patient developed a massive vitreous hemorrhage in the left eye, which precluded a view of the posterior segment. EUA, B-scan ultrasonography, and magnetic resonance imaging (MRI) of the brain and bilateral orbits were inconclusive for recurrence. Aqueous humor liquid biopsy, LBSeq4Kids, is an analytically validated College of American Pathologists / Clinical Laboratory Improvement Amendments (CAP/CLIA) laboratory test available for clinical use at Children's Hospital Los Angeles. Low pass whole-genome sequencing of aqueous humor cell-free DNA (cfDNA) demonstrated the presence of circulating tumor DNA consistent with an active intraocular recurrence. Enucleation of the left eye was performed and the histopathology confirmed active RB recurrence with massive choroidal invasion. Conclusions: Aqueous humor liquid biopsy can be used to guide clinical decision-making in RB, especially when there is a loss of fundus view and intraocular recurrence is suspected.

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• Copy number variant analysis improves diagnostic yield in a diverse pediatric exome sequencing cohort

  npj Genomic Medicine · 2025-02-21 · 3 citations

  articleOpen access

  Exome sequencing is the current standard for diagnosing Mendelian disorders; however, it is generally not considered the first-line test for detecting copy number variants (CNVs). We retrospectively investigated the additional diagnostic yield by performing concurrent CNV analysis using exome data in a large and diverse pediatric cohort. Patients were referred from various sources with variable phenotypes. Human Phenotype Ontology terms were used to prioritize variants for analysis. Ancestry and CNV analyses were performed using Somalier and NxClinical, respectively. A total of 1538 patients were tested, with the majority being Admixed Americans. Diagnostic CNVs were identified in 70 patients (4.6%), ranging from exonic deletions to large, unbalanced rearrangements, aneuploidies, and mosaic findings. While no significant differences were identified in diagnostic yield, or rates of negative or uncertain diagnoses, between ancestries, our study demonstrates the feasibility and increased yield of CNV analysis of exome data, across multiple phenotypes, referral sources, and ancestries.

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• Outcomes following radiotherapy for atypical teratoid/rhabdoid tumor in combination with surgery and intensive chemotherapy: A report from Children’s Oncology Group study ACNS0333

  Neuro-Oncology Pediatrics · 2025-11-25

  articleOpen access

  Abstract Background Children’s Oncology Group ACNS0333 treated atypical teratoid/rhabdoid tumor (ATRT) with surgery, chemotherapy (induction and consolidation) and radiation therapy (RT). M0 had focal RT and M+ had physician-selected focal RT or craniospinal (CSI). Methods Forty patients (29 M0, 11 M+) received RT. Pre-RT chemotherapy response was complete, partial, or stable disease. RT timing (age/stage-based) was pre-consolidation (RT-first) or post-consolidation (consolidation-first). Event-free survival (RT-EFS), overall survival (RT-OS), and cumulative incidence of local relapse (CILR) or distant relapse (RT-CIDR) were calculated. Analyses included log-rank tests and relative hazard rates with 95% confidence intervals to estimate proportional hazards regression. Results Four-year RT-EFS was 56.8% and 4-year RT-OS was 58.8% focal RT: 34 patients, CSI: 6 patients). A trend for superior RT-EFS for M+ compared to M0 (P = .0625, RHR 0.26; 95% CI 0.06-1.18) was shown. RT-EFS was improved for consolidation-first compared to RT-first timing (P = .037, RHR 0.43; 95% CI 0.13-1.37). Pre-RT chemotherapy response was associated with improved RT-EFS (P = .031) and RT-OS (P = .0069). Four-year RT-CILR was 7.84%; no differences in RT-CILR were shown for higher primary RT dose (≥5400 cGy, P = .38) or gross total resection (P = .80). 4-year RT-CIDR was 27.8% for M0 and 9.1% for M+ patients (P = .22). M+ had CSI (n = 6) or focal RT (n = 5). Fatal necrosis potentially-attributable to RT occurred in 3 RT-first patients (occuring either 1.6, 4.6, or 16.2 months post-treatment). Conclusions RT with intensive systemic therapy showed promising survival outcomes and effective primary disease control in ATRT. Sequencing RT prior to myeloblative chemotherapy, rather than post-consolidation, may be associated with increased risk of fatal radionecrosis.

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• Cerebrospinal Fluid from Cytology Supernatant as a Liquid Biopsy Specimen for Diagnosis and Surveillance for Pediatric Primary Central Nervous System Tumors

  medRxiv · 2025-10-08

  preprintOpen access

  Abstract Background Assessing circulating cell-free DNA (cfDNA) in cerebrospinal fluid (CSF) has been proposed as a promising alternative to tissue biopsy. Advances in cfDNA sequencing have further underscored the potential of CSF liquid biopsies. CSF is routinely collected for cytologic evaluation at diagnosis, and at recurrence in both pediatric and adult central nervous system (CNS) tumors. Methods As part of a pilot study, CSF specimens were prospectively collected from seven pediatric patients with primary CNS malignant tumors. When possible, CSF was collected fresh and/or from processed cytology specimens. Low-pass whole genome sequencing (LP-WGS) and next-generation sequencing (NGS) using a custom targeted sequencing panel were performed on the specimens to identify copy number alterations (CNAs), detect mutations, and estimate circulating tumor DNA (ctDNA) fractions. Results were compared with matched tumor tissue molecular profiles and corresponding imaging findings. Results Abnormalities in cfDNA were detected in four patients. Sequencing of CSF cytology supernatants demonstrated the presence of circulating tumor DNA with characteristic CNAs and mutations that matched what was seen the tumor tissue as well as the fresh CSF specimens. These studies also revealed tumor heterogeneity and genomic evolution over time. Conclusion This study demonstrates the feasibility of utilizing routinely discarded supernatants from CSF cytology specimens for LP-WGS and targeted NGS. Our approach optimizes the use of CSF that may be limited in pediatric patients as a reliable source for liquid biopsy-based genomic studies. Future research will be necessary to optimize the methodology to enable clinical implementation. Key points Combined low-pass whole genome sequencing (LP-WGS) and targeted next-generation sequencing (NGS) can detect circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) cytology supernatant samples. Our approach transforms clinically discarded specimens into a valuable and reliable source for liquid biopsy. LP-WGS and targeted NGS of CSF cytology-derived cell-free DNA (cfDNA) is more sensitive than CSF cytology for tumor detection at initial diagnosis and during surveillance. Importance of Study This report highlights the feasibility of utilizing supernatants from cerebrospinal fluid (CSF) cytology specimens that would normally be discarded for diagnosis and follow up for patients with pediatric primary central nervous system (CNS) tumors, using the LBSeq4Kids combined low-pass whole genome sequencing (LP-WGS) and targeted next-generation sequencing (NGS) liquid biopsy platform. It optimizes the use of limited clinical specimens and maximizes diagnostic and research potential, yet does not pose additional risk to patients by utilizing routinely collected cytology specimens. Identification of copy number alterations (CNAs) and DNA sequence variants detected in CSF-derived cell-free DNA from patients with high grade glioma and embryonal tumors can augment tissue-derived molecular analyses. CSF liquid biopsy approaches have the potential to transform clinical practice for improved diagnosis, risk stratification, and disease surveillance.

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• Abstract 986: <i>SMARCB1</i> missense mutants destabilize SWI/SNF complex stability and remodeling activity

  Cancer Research · 2025-04-21

  article

  SMARCB1-deficient cancers are aggressive and highly lethal pediatric malignancies. Loss of SMARCB1 protein expression, a subunit within the SWI/SNF chromatin remodeling complex, remains the key diagnostic feature of these cancers. This can occur through large deletions, balanced translocations, frameshift mutations, or truncating nonsense mutations. Here, we sought to understand the effect of missense mutations on the tumor suppressor function of SMARCB1 through deep mutational scanning (DMS). Specifically, we developed and introduced a library containing &amp;gt;99% of all possible SMARCB1 amino acid substitutions, including frameshift and nonsense mutants, into three pediatric SMARCB1-deficient cell lines (G401 - malignant rhabdoid tumor of the kidney, BT16 - atypical teratoid/rhabdoid tumor, and CCLF_PEDS9001_T1 - renal medullary carcinoma) and assessed cell fitness after 8-14 days. We observed broad mutational intolerance in three SMARCB1 domains: the winged-helix domain, intrinsically disordered region, and the RPT2 domain. Following our high-throughput study, we then focused on two highly enriched residues predicted to closely interact within the RPT2 domain of SMARCB1. We validated that specific missense mutations in these two residues mimic loss of function while retaining protein expression. Mechanistic studies revealed that these mutations destabilize the SWI/SNF complex, notably resulting in decreased affinity for SWI/SNF subunits known to be associated with cancer pathogenesis. This complex instability leads to diminished nucleosome remodeling and subsequent transcriptional deregulation. These findings challenge our current understanding of what a loss-of-function mutation means in the context of SMARCB1, suggesting that the absence of SMARCB1 protein expression may not be the sole indicator of SMARCB1 deficiency. Furthermore, this dataset provides a valuable resource for researchers to investigate key residues of SMARCB1 that may drive critical intermolecular interactions necessary for proper SWI/SNF complex assembly and function. Citation Format: Garrett W. Cooper, Benjamin Lee, Won Kim, Eliseo Salas, Yongdong Su, Victor Chen, Xiaoping Yang, Robert Lintner, Frederica Piccioni, Andrew Giacomelli, Thomas Howard, Karen Conneely, David Root, William Hahn, David Gorkin, Bo Liang, Jaclyn Biegel, Susan Chi, Andrew Hong. SMARCB1 missense mutants destabilize SWI/SNF complex stability and remodeling activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 986.

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• Abstract 1977: Implementation of a comprehensive clinical cfDNA analysis platform for aqueous humor liquid biopsy in retinoblastoma

  Cancer Research · 2025-04-21

  articleSenior author

  Introduction: The development of liquid biopsy testing based on sequencing analysis of cell-free DNA (cfDNA) has the potential to transform cancer care in pediatric tumors, which are characterized by a wide array of genomic alterations including copy number alterations (CNAs), sequence variants, epigenetic alterations, and structural rearrangements in tumor-associated genes. In patients with retinoblastoma where direct tumor biopsy is not possible due to the risk of tumor spread, aqueous humor (AH) is a rich source of cfDNA. Comprehensive cfDNA testing, combining a low pass whole genome sequencing (LP-WGS) assay to detect CNAs and a custom targeted sequencing panel (TSP) to detect mutations, can provide a highly effective platform to inform diagnosis, risk stratification, response to therapy, and surveillance in patients with retinoblastoma. LP-WGS Results: We validated a liquid biopsy LP-WGS assay, LBSeq4Kids, to detect CNAs in cfDNA from plasma, cerebrospinal fluid, or AH. Clinical testing has been performed for the past two years for diagnostic evaluation and monitoring response to therapy using AH from retinoblastoma patients. Thirty-six children with unilateral or bilateral retinoblastoma (44 eyes) underwent LBSeq4Kids LP-WGS analysis. CNAs were detected in 30/32 (94%) samples at diagnosis or recurrence. Serial sampling of 22/44 (50%) eyes was performed using a range of 1-10 samples per patient. Seventeen of those 22 (77%) eyes demonstrated clearance of CNAs with treatment. Five eyes showed persistence of abnormal profiles, necessitating enucleation of 2 eyes. Treatment and evaluation are ongoing for the remaining three eyes. Targeted Sequencing Panel Results: We are validating a custom cfDNA TSP to detect single nucleotide variants and small indels in the coding sequence of 136 genes and fusions involving EWSR1, FOXO1, and BRAF for patients with ocular disease, solid tumors and brain tumors. To date, 17 children (21 eyes) diagnosed with retinoblastoma have had TSP testing using AH. All eleven (100%) patients with germline variants demonstrated the same RB1 alterations in the AH using the panel. Six of these patients (55%) had a second somatic alteration in RB1 detected with the panel. Two of 11 (18%) with known germline RB1 mutations also demonstrated mutations in BCOR, ARID1A, or MSH6. Somatic variants in RB1, ARID1A and BCOR were detected in the remaining six patients with sporadic retinoblastoma. Targeted sequencing of the AH surveillance samples from these patients is in progress. Conclusion: Here we demonstrate clinical utility for aqueous humor liquid biopsy molecular testing as a complementary means of diagnosis and monitoring treatment response in patients with retinoblastoma. Continued surveillance of these patients is ongoing to monitor disease status and rule out recurrence, as well as identify novel prognostic biomarkers. Citation Format: Laura A. Kagami, Eirini Christodoulou, Venkata Yellapantula, Dong Xu, Cindy Fong, Dejerianne Ostrow, Liya Xu, Jesse Berry, Jaclyn A. Biegel. Implementation of a comprehensive clinical cfDNA analysis platform for aqueous humor liquid biopsy in retinoblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1977.

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Recent grants

• NIH Grant R01CA046274

  NIH · $5.0M · 2015

• NIH Grant P50HG000425

  NIH · $11.0M · 1997

• NIH Grant R21CA133173

  NIH · $407k · 2011

• NIH Grant P01DC002027

  NIH · $20.1M · 2005

• NIH Grant R24DK103001

  NIH · $1.7M · 2018

Frequent coauthors

• Alexander R. Judkins

  212 shared

• C. Hawkins

  University of Portsmouth

  160 shared

• Xiaowu Gai

  University of Southern California

  155 shared

• Darell D. Bigner

  Duke University

  154 shared

• Stefan M. Pfister

  University Hospital Heidelberg

  145 shared

• Diane K. Birks

  145 shared

• James T. Rutka

  Hospital for Sick Children

  144 shared

• R. Grundy

  Jilin University

  120 shared

Labs

• Jaclyn A. Biegel LabPI

Education

• PhD, Human Genetics

  University of Pittsburgh

  1981