TY - JOUR
T1 - Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence
AU - Xu, Lin
AU - Pierce, Joshua L.
AU - Sanchez, Angelica
AU - Chen, Kenneth S.
AU - Shukla, Abhay A.
AU - Fustino, Nicholas J.
AU - Stuart, Sarai H.
AU - Bagrodia, Aditya
AU - Xiao, Xue
AU - Guo, Lei
AU - Krailo, Mark D.
AU - Shaikh, Furqan
AU - Billmire, Deborah F.
AU - Pashankar, Farzana
AU - Bestrashniy, Jessica
AU - Oosterhuis, J. Wolter
AU - Gillis, Ad J.M.
AU - Xie, Yang
AU - Teot, Lisa
AU - Mora, Jaume
AU - Poynter, Jenny N.
AU - Rakheja, Dinesh
AU - Looijenga, Leendert H.J.
AU - Draper, Bruce W.
AU - Frazier, A. Lindsay
AU - Amatruda, James F.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85158061133
U2 - 10.1038/s41467-023-38378-9
DO - 10.1038/s41467-023-38378-9
M3 - Article
C2 - 37149691
AN - SCOPUS:85158061133
SN - 2041-1723
VL - 14
SP - 2636
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2636
ER -