Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors.
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.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Keith
JK
Killian
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, 3015, The Netherlands.
Lambert C J
LC
Dorssers
Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Britton
B
Trabert
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, 3015, The Netherlands.
Ad J M
AJ
Gillis
Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Michael B
MB
Cook
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yonghong
Y
Wang
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Joshua J
JJ
Waterfall
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Holly
H
Stevenson
Suburban Hospital Department of Pathology, Bethesda, Maryland 20814, USA.
William I
WI
Smith
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Natalia
N
Noyes
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Parvathy
P
Retnakumar
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, 3015, The Netherlands.
J Hans
JH
Stoop
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, 3015, The Netherlands.
J Wolter
JW
Oosterhuis
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Paul S
PS
Meltzer
Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Katherine A
KA
McGlynn
Department of Pathology, Erasmus MC-University Medical Center, Rotterdam, 3015, The Netherlands.
Leendert H J
LH
Looijenga
D019070:Cell Lineage; D065150:Cellular Reprogramming; D002868:Chromosomal Proteins, Non-Histone; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics*; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics*
D002868:Chromosomal Proteins, Non-Histone; C466105:DPPA3 protein, human; D000071317:Nanog Homeobox Protein; D011506:Proteins