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Characterizing Temporal Genomic Heterogeneity in Pediatric Low-Grade Gliomas

Lazow, Margot A
http://orcid.org/0000-0003-4362-4270
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623166967779353

Abstract Details

2021, MS, University of Cincinnati, Medicine: Clinical and Translational Research.
Recent discoveries have provided valuable insight into the genomic landscape of pediatric low-grade gliomas (LGGs) at diagnosis, facilitating molecularly targeted treatment. However, little is known about their temporal and therapy-related genomic heterogeneity. An adequate understanding of the evolution of pediatric LGGs’ genomic profiles over time is critically important in guiding decisions about targeted therapeutics and diagnostic biopsy at recurrence. Fluorescence in situ hybridization, mutation-specific immunohistochemistry, and/or targeted sequencing were performed on paired tumor samples from primary diagnostic and subsequent surgeries. Ninety-four tumor samples from 45 patients (41 with two specimens, four with three specimens) from three institutions underwent testing. Conservation of BRAF fusion, BRAFV600E mutation, and FGFR1 rearrangement status was observed in 100%, 98%, and 96% of paired specimens, respectively. No loss or gain of IDH1 mutations or NTRK2, MYB, or MYBL1 rearrangements were detected over time. Histologic diagnosis remained the same in all tumors, with no acquired H3K27M mutations or malignant transformation. Changes in CDKN2A deletion status at recurrence occurred in 11 patients (42%), with acquisition of hemizygous CDKN2A deletion in seven and loss in four. Shorter time to progression and shorter time to subsequent surgery were observed among patients with acquired CDKN2A deletions compared to patients without acquisition of this alteration (median time to progression: 5.5 versus 16.0 months [p=0.048]; median time to next surgery: 17.0 months versus 29.0 months [p=0.031]). Most targetable genetic aberrations in pediatric LGGs, including BRAF alterations, are conserved at recurrence and following chemotherapy or irradiation. However, changes in CDKN2A deletion status over time were demonstrated. Acquisition of CDKN2A deletion may define a higher risk subgroup of pediatric LGGs with a poorer prognosis. Given the potential for targeted therapies for tumors harboring CDKN2A deletions, biopsy at recurrence may be indicated in certain patients, especially those with rapid progression.
Scott Langevin, Ph.D. (Committee Chair)
Maryam Fouladi (Committee Member)
Adam Lane (Committee Member)
37 p.
Oncology
pediatric low-grade gliomas; genomics; paired; recurrence; BRAF; CDKN2A

Recommended Citations

Citations

  • Lazow, M. A. (2021). Characterizing Temporal Genomic Heterogeneity in Pediatric Low-Grade Gliomas [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623166967779353

    APA Style (7th edition)

  • Lazow, Margot. Characterizing Temporal Genomic Heterogeneity in Pediatric Low-Grade Gliomas. 2021. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623166967779353.

    MLA Style (8th edition)

  • Lazow, Margot. "Characterizing Temporal Genomic Heterogeneity in Pediatric Low-Grade Gliomas." Master's thesis, University of Cincinnati, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1623166967779353

    Chicago Manual of Style (17th edition)

ucin1623166967779353
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© 2021, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.