Am J Cancer Res 2012;2(2):153-167
Review Article
Molecular genetics of testicular germ cell tumors
Yuri Sheikine, Elizabeth Genega, Jonathan Melamed, Peng Lee, Victor E Reuter, Huihui Ye
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, Department of Pathology, Memorial
Sloan-Kettering Cancer Center, New York, NY, and Department of Pathology, New York University School of Medicine, New York,
NY, USA
Received January 16, 2012; accepted January 23, 2012; Epub February 2, 2012; Published February, 2012
Abstract: Testicular germ cell tumors (TGCT) are the most common malignancy in young men. While most TGCT are potentially
curable, approximately 5% of patients with TGCT may develop chemoresistance and die from the disease. This review article
summarizes current knowledge in genetics underlying the development, progression and chemoresistance of TGCT. Most
post-pubertal TGCT originate from intratubular germ cell neoplasia unclassified (IGCNU), which are transformed fetal
gonocytes. Development of IGCNU may involve aberrantly activated KITLG/KIT pathway and overexpression of embryonic
transcription factors such as NANOG and POU5F1, which leads to suppression of apoptosis, increased proliferation, and
accumulation of mutations in gonocytes. Invasive TGCT consistently show gain of chromosome 12p, typically isochromosome
12p. Single gene mutations are uncommon in TGCT. KIT, TP53, KRAS/NRAS, and BRAF are genes most commonly mutated in
TGCT and implicated in their pathogenesis. Different histologic subtypes of TGCT process different gene expression profiles
and reflect different directions of differentiation. Their distinct gene expression profiles are likely caused by epigenetic regulation,
in particular DNA methylation, but not by gene copy number alterations. Resistance of TGCT to chemotherapy has been linked to
karyotypic aberrations, single-gene mutations, and epigenetic regulation of gene expression in small-scale studies. The study of
TGCT genetics could ultimately translate into development of new molecular diagnostic and therapeutic modalities for these
tumors and improve the care of patients with these malignancies. (AJCR00000104).
Keywords: Pathology, genetics, testis, germ cell tumor
Address all correspondence to:
Huihui Ye, MD
Department of Pathology
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02120
Tel: 617-667-5828
Fax: 617-975-5620
E-mail: hye@bidmc.harvard.edu
Review Article
Molecular genetics of testicular germ cell tumors
Yuri Sheikine, Elizabeth Genega, Jonathan Melamed, Peng Lee, Victor E Reuter, Huihui Ye
Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, Department of Pathology, Memorial
Sloan-Kettering Cancer Center, New York, NY, and Department of Pathology, New York University School of Medicine, New York,
NY, USA
Received January 16, 2012; accepted January 23, 2012; Epub February 2, 2012; Published February, 2012
Abstract: Testicular germ cell tumors (TGCT) are the most common malignancy in young men. While most TGCT are potentially
curable, approximately 5% of patients with TGCT may develop chemoresistance and die from the disease. This review article
summarizes current knowledge in genetics underlying the development, progression and chemoresistance of TGCT. Most
post-pubertal TGCT originate from intratubular germ cell neoplasia unclassified (IGCNU), which are transformed fetal
gonocytes. Development of IGCNU may involve aberrantly activated KITLG/KIT pathway and overexpression of embryonic
transcription factors such as NANOG and POU5F1, which leads to suppression of apoptosis, increased proliferation, and
accumulation of mutations in gonocytes. Invasive TGCT consistently show gain of chromosome 12p, typically isochromosome
12p. Single gene mutations are uncommon in TGCT. KIT, TP53, KRAS/NRAS, and BRAF are genes most commonly mutated in
TGCT and implicated in their pathogenesis. Different histologic subtypes of TGCT process different gene expression profiles
and reflect different directions of differentiation. Their distinct gene expression profiles are likely caused by epigenetic regulation,
in particular DNA methylation, but not by gene copy number alterations. Resistance of TGCT to chemotherapy has been linked to
karyotypic aberrations, single-gene mutations, and epigenetic regulation of gene expression in small-scale studies. The study of
TGCT genetics could ultimately translate into development of new molecular diagnostic and therapeutic modalities for these
tumors and improve the care of patients with these malignancies. (AJCR00000104).
Keywords: Pathology, genetics, testis, germ cell tumor
Address all correspondence to:
Huihui Ye, MD
Department of Pathology
Beth Israel Deaconess Medical Center
330 Brookline Avenue
Boston, MA 02120
Tel: 617-667-5828
Fax: 617-975-5620
E-mail: hye@bidmc.harvard.edu
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American Journal of Cancer Research
| ISSN: 2156-6976 |