High Comorbidity of Pediatric Cancers in Patients with Birth Defects: Insights from Whole Genome Sequencing Analysis of Copy Number Variations.

Autor: Qu HQ; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Glessner JT; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Qu J; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Liu Y; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Watson D; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Chang X; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Saeidian AH; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Qiu H; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Mentch FD; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Connolly JJ; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA., Hakonarson H; Center for Applied Genomics (CAG), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104, USA; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA; Division of Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA; Faculty of Medicine, University of Iceland, Reykjavik, Iceland. Electronic address: hakonarson@chop.edu.
Jazyk: angličtina
Zdroj: Translational research : the journal of laboratory and clinical medicine [Transl Res] 2024 Apr; Vol. 266, pp. 49-56. Date of Electronic Publication: 2023 Nov 19.
DOI: 10.1016/j.trsl.2023.11.004
Abstrakt: Background: Patients with birth defects (BD) exhibit an elevated risk of cancer. We aimed to investigate the potential link between pediatric cancers and BDs, exploring the hypothesis of shared genetic defects contributing to the coexistence of these conditions.
Methods: This study included 1454 probands with BDs (704 females and 750 males), including 619 (42.3%) with and 845 (57.7%) without co-occurrence of pediatric onset cancers. Whole genome sequencing (WGS) was done at 30X coverage through the Kids First/Gabriella Miller X01 Program.
Results: 8211 CNV loci were called from the 1454 unrelated individuals. 191 CNV loci classified as pathogenic/likely pathogenic (P/LP) were identified in 309 (21.3%) patients, with 124 (40.1%) of these patients having pediatric onset cancers. The most common group of CNVs are pathogenic deletions covering the region ChrX:52,863,011-55,652,521, seen in 162 patients including 17 males. Large recurrent P/LP duplications >5MB were detected in 33 patients.
Conclusions: This study revealed that P/LP CNVs were common in a large cohort of BD patients with high rate of pediatric cancers. We present a comprehensive spectrum of P/LP CNVs in patients with BDs and various cancers. Notably, deletions involving E2F target genes and genes implicated in mitotic spindle assembly and G2/M checkpoint were identified, potentially disrupting cell-cycle progression and providing mechanistic insights into the concurrent occurrence of BDs and cancers.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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