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; James F Amatruda

doi:10.1038/s41467-023-38378-9

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

Nat Commun. 2023 May 6;14(1):2636. doi: 10.1038/s41467-023-38378-9.

Authors

Lin Xu^#^{1

2

3}, Joshua L Pierce^#⁴, Angelica Sanchez^#⁴, Kenneth S Chen⁴, Abhay A Shukla⁴, Nicholas J Fustino^{4

5}, Sarai H Stuart⁴, Aditya Bagrodia^{6

7}, Xue Xiao^{8

9}, Lei Guo^{8

9}, Mark D Krailo^{10

11}, Furqan Shaikh¹², Deborah F Billmire¹³, Farzana Pashankar¹⁴, Jessica Bestrashniy¹⁵, J Wolter Oosterhuis¹⁶, Ad J M Gillis¹⁶, Yang Xie^{8

9

17}, Lisa Teot¹⁸, Jaume Mora¹⁹, Jenny N Poynter¹⁵, Dinesh Rakheja^{4

20}, Leendert H J Looijenga¹⁶, Bruce W Draper²¹, A Lindsay Frazier²², James F Amatruda^{23

24

25}

Affiliations

¹ Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. lin.xu@utsouthwestern.edu.
² 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.
³ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA. lin.xu@utsouthwestern.edu.
⁴ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Blank Children's Hospital, Des Moines, IA, USA.
⁶ Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁷ Department of Urology, University of California San Diego, San Diego, CA, USA.
⁸ Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁹ Department of Population & Data Sciences, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁰ Department of Preventative Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
¹¹ Children's Oncology Group, Monrovia, CA, USA.
¹² The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹³ Riley Hospital for Children, Indianapolis, IN, USA.
¹⁴ Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA.
¹⁵ Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
¹⁶ Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
¹⁷ Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁸ Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
¹⁹ Sant Joan de Déu Barcelona Children's Hospital, Barcelona, Spain.
²⁰ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²¹ Department of Molecular and Cellular Biology, University of California Davis, Davis, CA, USA.
²² Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
²³ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA. jamatruda@chla.usc.edu.
²⁴ Department of Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. jamatruda@chla.usc.edu.
²⁵ Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. jamatruda@chla.usc.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Female
Genomics
Humans
Infant
Infant, Newborn
Male
Neoplasms, Germ Cell and Embryonal* / genetics
Teratoma* / pathology
Testicular Neoplasms* / genetics
Testicular Neoplasms* / pathology
Wnt Signaling Pathway / genetics
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding