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

Lin Xu (), Joshua L. Pierce, Angelica Sanchez, Kenneth S. Chen, Abhay A. Shukla, Nicholas J. Fustino, Sarai H. Stuart, Aditya Bagrodia, Xue Xiao, Lei Guo, Mark D. Krailo, Furqan Shaikh, Deborah F. Billmire, Farzana Pashankar, Jessica Bestrashniy, J. Wolter Oosterhuis, Ad J. M. Gillis, Yang Xie, Lisa Teot, Jaume Mora, Jenny N. Poynter, Dinesh Rakheja, Leendert H. J. Looijenga, Bruce W. Draper, A. Lindsay Frazier and James F. Amatruda ()
Additional contact information
Lin Xu: University of Texas Southwestern Medical Center
Joshua L. Pierce: University of Texas Southwestern Medical Center
Angelica Sanchez: University of Texas Southwestern Medical Center
Kenneth S. Chen: University of Texas Southwestern Medical Center
Abhay A. Shukla: University of Texas Southwestern Medical Center
Nicholas J. Fustino: University of Texas Southwestern Medical Center
Sarai H. Stuart: University of Texas Southwestern Medical Center
Aditya Bagrodia: University of Texas Southwestern Medical Center
Xue Xiao: University of Texas Southwestern Medical Center
Lei Guo: University of Texas Southwestern Medical Center
Mark D. Krailo: University of Southern California Keck School of Medicine
Furqan Shaikh: The Hospital for Sick Children, University of Toronto
Deborah F. Billmire: Riley Hospital for Children
Farzana Pashankar: Yale University School of Medicine
Jessica Bestrashniy: University of Minnesota
J. Wolter Oosterhuis: Princess Máxima Center for Pediatric Oncology
Ad J. M. Gillis: Princess Máxima Center for Pediatric Oncology
Yang Xie: University of Texas Southwestern Medical Center
Lisa Teot: Boston Children’s Hospital
Jaume Mora: Sant Joan de Déu Barcelona Children’s Hospital
Jenny N. Poynter: University of Minnesota
Dinesh Rakheja: University of Texas Southwestern Medical Center
Leendert H. J. Looijenga: Princess Máxima Center for Pediatric Oncology
Bruce W. Draper: University of California Davis
A. Lindsay Frazier: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
James F. Amatruda: Children’s Hospital Los Angeles

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38378-9

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