DNA methylation analysis reveals distinct methylation signatures in pediatric germ cell tumors

Abstract

BackgroundAberrant DNA methylation is a prominent feature of many cancers, and may be especially relevant in germ cell tumors (GCTs) due to the extensive epigenetic reprogramming that occurs in the germ line during normal development.MethodsWe used the Illumina GoldenGate Cancer Methylation Panel to compare DNA methylation in the three main histologic subtypes of pediatric GCTs (germinoma, teratoma and yolk sac tumor (YST); N = 51) and used recursively partitioned mixture models (RPMM) to test associations between methylation pattern and tumor and demographic characteristics. We identified genes and pathways that were differentially methylated using generalized linear models and Ingenuity Pathway Analysis. We also measured global DNA methylation at LINE1 elements and evaluated methylation at selected imprinted loci using pyrosequencing.ResultsMethylation patterns differed by tumor histology, with 18/19 YSTs forming a distinct methylation class. Four pathways showed significant enrichment for YSTs, including a human embryonic stem cell pluripotency pathway. We identified 190 CpG loci with significant methylation differences in mature and immature teratomas (q < 0.05), including a number of CpGs in stem cell and pluripotency-related pathways. Both YST and germinoma showed significantly lower methylation at LINE1 elements compared with normal adjacent tissue while there was no difference between teratoma (mature and immature) and normal tissue. DNA methylation at imprinted loci differed significantly by tumor histology and location.ConclusionUnderstanding methylation patterns may identify the developmental stage at which the GCT arose and the at-risk period when environmental exposures could be most harmful. Further, identification of relevant genetic pathways could lead to the development of new targets for therapy.

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

“…4A). YSTs have been previously reported to harbor an overall hypermethylated profile (Amatruda et al 2013;Furukawa et al 2009), although we find strong lineage-specific hypomethylation as well. We now further interpret the YST methylome to have subtype-specific, differentiation-level programming with some unique homology with trophoblast, yet not entirely convergent with it.…”

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

“…TEs are heritable mobile genetic elements that can contribute to diseases such as cancer (100,103). Indeed, altered methylation levels of TEs are commonly found in human tumors such as TGCTs (seminomas and nonseminomas) (33,(104)(105)(106). TE regulation is also under the control of RNA editors (ADARs, APOBECs) such as the potent TGCT modifier APOBEC1 (107), emphasizing the role of TEs in TGCT risk and suggesting a functional link between AGO2 siRNAs and APO-BEC1-A1CF in teratocarcinogenesis.…”

An oncofetal and developmental perspective on testicular germ cell cancer

“…2B). In this perspective, epigenetic (de)regulation is a tempting bridge between genetics and environment [94,176,181], even trans-generationally [180,182]. Genvironmental disturbance results in a spectrum of clinical manifestations associated with increased risk of TGCC that has been baptized testicular dysgenesis syndrome (TDS) [183,184] (Fig.…”