Bibliographic Details
| Title: |
Evaluation of Hi-C Sequencing for Detection of Gene Fusions in Hematologic and Solid Tumor Pediatric Cancer Samples. |
| Authors: |
Schmitt, Anthony D.1 (AUTHOR) anthony@arimagenomics.com, Sikkink, Kristin1 (AUTHOR) shadi@arimagenomics.com, Ahmed, Atif A.2 (AUTHOR), Melnyk, Shadi1 (AUTHOR) bretreid10@gmail.com, Reid, Derek1 (AUTHOR) vanmeter.logan@gmail.com, Van Meter, Logan1 (AUTHOR), Guest, Erin M.3,4 (AUTHOR), Lansdon, Lisa A.5,6 (AUTHOR) ipushel@cmh.edu, Pastinen, Tomi4,5 (AUTHOR), Pushel, Irina5 (AUTHOR), Yoo, Byunggil5,6 (AUTHOR), Farooqi, Midhat S.4,5,6 (AUTHOR) anthony@arimagenomics.com |
| Source: |
Cancers. Sep2024, Vol. 16 Issue 17, p2936. 14p. |
| Subject Terms: |
*LEUKEMIA diagnosis, *TUMORS in children, *HEMATOLOGIC malignancies, *GENOMICS, *SARCOMA, *CHROMOSOME abnormalities, *GENETIC polymorphisms, *GENES, *MYELOID leukemia, *RHABDOMYOSARCOMA, *SEQUENCE analysis, *MOLECULAR diagnosis, DIAGNOSIS of tumors in children |
| Abstract: |
Simple Summary: Genomic rearrangements are chromosomal abnormalities that alter the arrangement of genes and are important for diagnosing multiple cancer types and guiding therapy selection. However, current diagnostic tests may not detect all genomic rearrangements. Hi-C sequencing is a promising new method for detecting genomic rearrangements. First, we examined whether Hi-C can detect known genomic rearrangements in pediatric leukemia and sarcoma specimens. Next, we evaluated whether Hi-C can detect genomic rearrangements that were not found using standard diagnostic testing. Hi-C showed complete agreement with other diagnostic methods in identifying known rearrangements. Hi-C also detected previously unknown genomic rearrangements in 5/11 pediatric leukemia cases that could impact diagnosis, prognosis, or treatment choices. These data suggest Hi-C could be beneficial for medical diagnostic testing of pediatric cancers, but more extensive clinical validation is needed. Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens. Archived viable and non-viable frozen leukemic cells and formalin-fixed paraffin-embedded (FFPE) tumor specimens were analyzed. Pediatric acute myeloid leukemia (AML) and alveolar rhabdomyosarcoma (A-RMS) specimens with known genomic rearrangements were subjected to Hi-C to assess analytical concordance. Subsequently, a discovery cohort consisting of AML and acute lymphoblastic leukemia (ALL) cases without known genomic rearrangements based on prior clinical diagnostic testing was evaluated to determine whether Hi-C could detect rearrangements. Using a standard sequencing depth of 50 million raw read-pairs per sample, or approximately 5X raw genomic coverage, we observed 100% concordance between Hi-C and previous clinical cytogenetic and molecular testing. In the discovery cohort, a clinically relevant gene fusion was detected in 45% of leukemia cases (5/11). This study provides an institutional proof of principle evaluation of Hi-C sequencing to medical diagnostic testing as it identified several clinically relevant rearrangements, including those that were missed by current clinical testing workflows. [ABSTRACT FROM AUTHOR] |
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