Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline
Keren Cheng,
Yasunari Seita,
Eoin C. Whelan,
Ryo Yokomizo,
Young Sun Hwang,
Antonia Rotolo,
Ian D. Krantz,
Jill P. Ginsberg,
Thomas F. Kolon,
Priti Lal,
Xunda Luo,
Phillip M. Pierorazio,
Rebecca L. Linn,
Sandra Ryeom,
Kotaro Sasaki
Affiliations
Keren Cheng
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Yasunari Seita
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Eoin C. Whelan
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Ryo Yokomizo
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Young Sun Hwang
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Antonia Rotolo
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA
Ian D. Krantz
Division of Human Genetics, The Roberts Individualized Medical Genetics Center, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
Jill P. Ginsberg
Department of Pediatrics, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
Thomas F. Kolon
Division of Urology, The Children’s Hospital of Philadelphia, 3500 Civic Center Boulevard, Philadelphia, PA 19104, USA
Priti Lal
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA
Xunda Luo
Department of Pathology and Laboratory Medicine, University of Pennsylvania Presbyterian Medical Center, 51 North 39th Street, Philadelphia, PA 19104, USA
Phillip M. Pierorazio
Division of Urology, University of Pennsylvania Presbyterian Medical Center, 3737 Market St. 4th Floor, Philadelphia, PA 19104, USA
Rebecca L. Linn
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA; Department of Pathology, The Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104, USA
Sandra Ryeom
Department of Surgery, Columbia University Irving Medical Center, 630 W. 168th Street, P&S 17-409, New York, NY 10032, USA
Kotaro Sasaki
Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA; Corresponding author
Summary: Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.
