Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Autor: Xu L; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. lin.xu@utsouthwestern.edu.; Department of Population & Data Sciences, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA. lin.xu@utsouthwestern.edu.; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. lin.xu@utsouthwestern.edu., Pierce JL; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Sanchez A; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Chen KS; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Shukla AA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Fustino NJ; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Blank Children's Hospital, Des Moines, IA, USA., Stuart SH; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Bagrodia A; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Urology, University of California San Diego, San Diego, CA, USA., Xiao X; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Population & Data Sciences, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA., Guo L; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Population & Data Sciences, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA., Krailo MD; Department of Preventative Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.; Children's Oncology Group, Monrovia, CA, USA., Shaikh F; The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada., Billmire DF; Riley Hospital for Children, Indianapolis, IN, USA., Pashankar F; Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA., Bestrashniy J; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Oosterhuis JW; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Gillis AJM; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Xie Y; Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Population & Data Sciences, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Teot L; Department of Pathology, Boston Children's Hospital, Boston, MA, USA., Mora J; Sant Joan de Déu Barcelona Children's Hospital, Barcelona, Spain., Poynter JN; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA., Rakheja D; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Looijenga LHJ; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Draper BW; Department of Molecular and Cellular Biology, University of California Davis, Davis, CA, USA., Frazier AL; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA., Amatruda JF; Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA. jamatruda@chla.usc.edu.; Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. jamatruda@chla.usc.edu.; Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. jamatruda@chla.usc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 May 06; Vol. 14 (1), pp. 2636. Date of Electronic Publication: 2023 May 06.
DOI: 10.1038/s41467-023-38378-9
Abstrakt: Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.
(© 2023. The Author(s).)
Databáze: MEDLINE
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