53. Clinical whole exome/whole transcriptome (WES/WTS) analysis detects copy number and structural rearrangements important

Aly Abdelkareem

Hussam Al-Kateb

Dr. Hussam Al-Kateb received his Ph.D in Biology (Human Molecular Genetics) with honors from the University of Heidelberg, Germany. He then did research in complex genetic disorders for 3 years at the Hospital for Sick Children in Toronto, Canada. After that he moved to the US and received his training at the University Hospitals and Case Western University in Clinical Cytogenomic and Clinical Molecular Genomics and is dual boarded by ABMGG in both specialties. Dr. Al-Kateb took a faculty position at Washington University School of Medicine as Assistant Professor and Associate Director for the Cytogenomic and Molecular Pathology labs where he served for five years. Dr. Al-Kateb was then recruited to the University of Arizona as an Associate Professor and Banner Health System where he assumed directorship of the molecular genomic and cytogenmic labs until 2018 where he was recruited to Cincinnati Children’s Hospital to serve as the Director of Precision Oncology Laboratory. He next was recruited to SEMA4 in 2019 and has since then been serving as the Division Head for Hematological Malignancies, and since 2020 also as the Director of the Somatic Curation Team. Dr. Al-Kateb has extensive expertise in technical, operational, and clinical molecular and cytogenomics and has published over 60 peer-reviewed articles and abstracts in both in constitutional and somatic disorders, as well as on technical aspects of NGS. Dr. Al-Kateb trained fellows in ABMGG-offered clinical molecular and cytogenomics, LGG training programs, as well as molecular genetic pathology (MGP) training program.


Hussam Al-Kateb

SEMA4, Branford, CT, USA

Background: Chromosomal copy number alterations (CNAs) and structural rearrangements (SR) are a key part of risk stratification and management of patients with MM. We developed a clinical paired tumor/normal WES/WTS assay that detects CNAs at one-copy difference from focal to whole genome, and gene fusion at 20% and 10% limit of detection, respectively.

Patients and Methods: We performed WES/WTS analysis utilizing DNA/RNA extracted from CD138+ enriched cells and buccal swab from 92 MM patients. Plasma cell content was not available for most cases. We compared the detection of CNAs, and SR with other techniques currently in use including FISH, arrays and molecular analysis.

Results: Molecular alterations (MA) were present in 82/92(89.1%) cases, whereas 65/92(69.5%) cases had CNAs. In cases with CNAs (indicating sufficient tumor content), deletions of (1p32), (1p12), or both were detected in 7(10.8%), 12(18.5%), and 5(7.7%) cases, respectively. Gain of (1q22), and hyperdiploidy were detected in 19(29.2%) and 32(49.2%), respectively. Deletions of 13q, 14q, 16q, and 17p(TP53) were detected in 32(49.2%), 14(21.6%), 16(24.6%), and 13(20%) cases, respectively. In cases with MA, 10/82(10.8%), and 3(3.6%) cases had TP53 mono and bi-allelic inactivation, respectively.

Translocations (4;14)(p16;q32)(IGH::NSD2/FGFR3) and t(14;16)(q32;q23)(IGH::MAF) were detected in 11(11.9%), and 3(3.7%) cases with MA, respectively. Overexpression of CCND1 (research use only) was observed in 8/82(9.7%) cases.

Discussion: Our WES/WTS detected abnormalities in this series similarly to what has been reported by techniques currently needed in combination such as FISH, arrays or molecular analysis. By incorporating RNA expression analysis, WES/WTS may reliably detect all clinically-relevant alterations in MM.