Germ Cell Tumor Explorer


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Germ cell tumors (GCTs) are malignant cancers that arise from embryonic precursors known as Primordial Germ Cells. GCTs occur in neonates, children, adolescents and young adults and can occur in the testis, the ovary or extragonadal sites. Because GCTs arise from pluripotent cells, the tumors can exhibit a wide range of different histologies. Current cisplatin-based combination therapies cure most patients, however at the cost of significant toxicity to normal tissues. While GWAS studies and genomic analysis of human GCTs have uncovered some somatic mutations and loci that might confer tumor susceptibility, little is still known about the exact mechanisms that drive tumor development.

Background on Germ Cell Tumor

Both childhood and adolescent/adult GCTs are thought to originate from Primordial Germ Cells (PGCs). Owing to the pluripotent nature of these cells, GCTs can take on a variety of different histologic fates. GCTs in which the PGCs retain pluripotency and do not differentiate are known as seminomas (also called ‘dysgerminomas’ in females and ‘germinomas’ when occurring in the CNS). In contrast, GCTs in which the cells take on a variety of differentiation states are designated non-seminomas, of which embryonal carcinoma is thought to represent the stem cell component. GCTs differentiated to somatic cell lineages (endoderm, mesoderm, and ectoderm) are known as teratomas. Finally, GCTs may take on extraembryonic differentiation resembling the fetal yolk sac (yolk sac tumors) or the placenta (choriocarcinoma).
The histology of GCTs is similar in both males and females, whether occurring in the testis, ovary or extragonadal sites, implying origin from a common precursor cell. However, there are some epidemiologic differences in the incidence of different types of GCT. In males there are two peaks of testicular GCT incidence, one in early childhood at age 3-4, and a second, much larger peak that begins at puberty and is maximal at around age 30. In females, there is an early peak from age 0-2 representing the incidence of sacrococcygeal teratoma, an extragonadal GCT, in newborns and infants. Beginning at age 5-6, the incidence of ovarian GCT increases with age, becoming maximal at age 20-25
While the overall incidence of GCT (about 12,500 cases/year in the USA) is lower than that of common epithelial cancers such as lung, breast and prostate cancer, testicular GCT is the most common cancer and the leading cause of cancer death in young men. The incidence of GCT is increasing around the world, for unknown reasons. There are several known risk factors that increase the risk of developing testicular germ cell tumors. They include but are not limited to disorders of sexual development (DSD), gonadal dysgenesis, cryptorchidism (undescended testis), familial background, environmental exposure, and genetic association. Familial risk can increase the risk of developing GCT 4-fold in a male with a father who had GCT or up to 9-fold in a male whose brother had GCTs. The incidence of GCT varies widely in different geographic regions, leading to the idea that the environment may strongly influence risk for testicular GCT.
There are also important age-dependent differences in GCT histologic spectrum. Type I GCTs occur in infants and children and consist of teratomas and yolk sac tumors (YSTs). Type II tumors in adolescents and adults have more diverse histology, and include seminomas, non-seminomas or mixed tumors containing both seminomatous and non-seminomatous elements. Based on differing epidemiology, clinical outcome and histologic spectrum, GCTs in young children may be biologically distinct from GCTs occurring in older (post-pubertal) populations.

Molecular Genetics of Germ Cell Tumors

Based on differing epidemiology, clinical outcome and histologic spectrum, GCTs in young children may be biologically distinct from GCTs occurring in older (post-pubertal) populations.
This idea is increasingly supported by molecular evidence. Whereas Type I tumors show variable Loss of Imprinting (LOI) at loci such as IGF2 and H19, adult-type GCTs tend to show complete erasure of imprinting. This result is interesting, because it implies that Type I GCTs may arise at an earlier stage of PGC development, since PGCs undergo erasure of imprinting during early development, and this erasure is largely completed by the end of PGC migration. Cytogenetic data consistently show loss of Chromosome 1p and 6q in Type I tumors, while Type II tumors also commonly exhibit amplification of Chromosome 12p. More recently, studies directly comparing the gene expression patterns of pediatric and adult GCTs have demonstrated distinct transcriptional profiles in tumors of similar histology arising in different age groups (for example, in yolk sac tumors of children vs. yolk sac tumors of adolescent/adults) . Taken together, these studies support the notion that different biological mechanisms may drive childhood and adolescent/adult germ cell tumorigenesis.
Compared to many other solid malignancies, relatively few somatic mutations have been described in GCTs. This lack of knowledge inhibits the development of targeted therapy that could provide an alternative or adjunct to standard chemotherapy. Amplification of Chromosome 12p is a pathognomonic feature of adolescent/adult GCTs, but no genes in this region have definitively been linked to germ cell tumorigenesis. The most commonly reported mutated gene is KIT, a tyrosine kinase growth factor receptor that plays important roles in germ cell development. Mutations have also been reported in NRAS and KRAS, signaling components of the MAP kinase pathway that act downstream of KIT. Central Nervous System GCTs exhibit KIT and RAS mutations. Somatic mutations in BRAF, another MAP kinase pathway member, have been associated with cisplatin resistance in adult TGCTs. More recently, exome sequencing of TGCT identified somatic mutations in several genes including CIITA, NEB, PDGFRA, WHSC1 and SUPT6H. A larger study of 42 adult TGCTs identified somatic mutations in CDC27 and mutations in XRCC2 associated with cisplatin resistance. To date, the mutation spectrum of Type I GCTs has not been reported.
A number of genome-wide association studies (GWAS) have been conducted in men with TGCT, resulting in the identification of a large number of novel germ cell tumor susceptibility loci. In 2009, two groups reported strong linkage of GCT susceptibility to loci on chromosomes 5, 6 and 12, suggesting roles for SPRY4 and KITLG, both components of receptor tyrosine kinase signaling, as well as for the pro-apoptotic BAK1 gene. A follow-up study by Turnbull and co-workers identified additional susceptibility loci near the DMRT1, TERT and ATF7IP genes. The studies have subsequently been replicated in other patient populations. More recently, further GWAS studies have identified new candidate GCT susceptibility loci, including genes with potential roles in telomere regulation, such as PITX1, or germ cell development, such as TEX14, RAD51C, PRDM14 and DAZL.