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

Abstract

Testicular germ cell tumors (TGCTs) share germline ancestry but diverge phenotypically and clinically as seminoma (SE) and nonseminoma (NSE), the latter including the pluripotent embryonal carcinoma (EC) and its differentiated derivatives, teratoma (TE), yolk sac tumor (YST), and choriocarcinoma. Epigenomes from TGCTs may illuminate reprogramming in both normal development and testicular tumorigenesis. Herein we investigate pure-histological forms of 130 TGCTs for conserved and subtype-specific DNA methylation, including analysis of relatedness to pluripotent stem cell (ESC, iPSC), primordial germ cell (PGC), and differentiated somatic references. Most generally, TGCTs conserve PGC-lineage erasure of maternal and paternal genomic imprints and DPPA3 (also known as STELLA); however, like ESCs, TGCTs show focal recurrent imprinted domain hypermethylation. In this setting of shared physiologic erasure, NSEs harbor a malignancy-associated hypermethylation core, akin to that of a diverse cancer compendium. Beyond these concordances, we found subtype epigenetic homology with pluripotent versus differentiated states. ECs demonstrate a striking convergence of both CpG and CpH (non-CpG) methylation with pluripotent states; the pluripotential methyl-CpH signature crosses species boundaries and is distinct from neuronal methyl-CpH. EC differentiation to TE and YST entails reprogramming toward the somatic state, with loss of methyl-CpH but de novo methylation of pluripotency loci such as NANOG. Extreme methyl-depletion among SE reflects the PGC methylation nadir. Adjacent to TGCTs, benign testis methylation profiles are determined by spermatogenetic proficiency measured by Johnsen score. In sum, TGCTs share collective entrapment in a PGC-like state of genomic-imprint and DPPA3 erasure, recurrent hypermethylation of cancer-associated targets, and subtype-dependent pluripotent, germline, or somatic methylation.

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…The epigenetic landscape of TGCTs is very determinant in these tumors, from their genesis to progression, recapitulating developmental events. DNA and histone modifications in these tumors are quite distinct, SEs being hypomethylated and more acetylated, while NSs show hypermethylation and increased acetylation [176,177]. Given their supranumerical X-chromosome content, the expression of XIST, triggered by demethylation of its promoter, is maintained in these tumors, contrarily to somatic cancers [178], which may be used as a liquid biopsy marker of the disease [179].…”

Molecular Heterogeneity and Early Metastatic Clone Selection in Testicular Germ Cell Cancer Development

“…3). This was expected because of EC being the stem cell component of all differentiated NS elements in the primary NS and different EC precursors providing independent lineages of differentiated cells (5,34). A typical example is provided by the T3209 EB23 which resembles an early developing embryo derived from a single EC with a different genomic make-up ( Supplementary Fig.…”

“…About 50% of the TGCC patients present with a NS, that can be composed of different histological elements, embryonal carcinoma (EC), teratoma (TE), yolk sac tumor (YST), and choriocarcinoma (ChC), either pure or mixed. The EC is the pluripotent stem cell component of NS, which can mimic normal early embryogenesis including the formation of so called embryonal bodies (EB), and thereby give rise to all differentiated components [3][4][5] .…”

“…So far, detailed studies into the molecular profile of TGCCs and their progression stages were focused on specific genes, like KIT 7 and TP53 [8][9][10] , and on the chromosomal constitution. Analyses have revealed many changes in the (relative) number of individual chromosomes in the different tumor components 5,[11][12][13][14][15][16] . Gain of the short arm of chromosome 12 is a hall mark of (invasive) TGCCs 17 , but as yet no causative gene (s) have been identified.…”

“…So far, detailed studies into the molecular profile of TGCCs and their progression stages were focused on specific genes, like KIT (7) and TP53 (8-10), and on the chromosomal constitution. Analyses have revealed many changes in the (relative) number of individual chromosomes in the different tumor components (5,(11)(12)(13)(14)(15)(16). Gain of the…”