Testicular Germ Cell Tumors: A Cytogenomic Update

Testicular germ cell tumors (TGCT) are a rare neoplasia but are still the most common malignancy in males between the ages of 15 and 44. TGCTs can be divided into two main types: Seminomas (SE) and non-seminomas (NS), the latter with an earlier age of onset and a worst prognosis. One of the most consistent features of TGCTs is the gain of material in the short arm of chromosome 12, that occurs in almost 100% of TGCT cases; 80% of them involve the formation of an isochromosome of the short arm i(12p). This might be the key step that allows the lesion to progress from a germ cell neoplasia in situ (GCNIS), which is a microscopic finding preceding the TGCT and without gain in 12p, to a TGCT. Some tumors, specially SE, present a more restricted amplification of certain 12p regions such as the 12p11.2-12.1 amplicon instead of the i(12p). The mechanism that associates the gain of 12p and the development of invasiveness is not yet well understood but it is believed a number of genes are involved, including DPPA3/STELLA, SOX5, PHC2, ATF7IP and proto-oncogenes Cyclin D2 and KRAS. Genome wide association studies have allowed us to acquire a better knowledge of the pathogenesis of this type of tumor, in which multiple genes show an increase in copy numbers, higher expression or activating mutations in genes related to the KIT/ KITLG pathway like KRAS, BRAF or KIT and KITLG itself. A less frequent subtype of TGCT found in older patients are spermatocytic tumors (ST). It does not develop from a GCNIS and presents a gain of genetic material in chromosome 9 instead of 12. It is believed the overexpression of the gene DMRT1, at 9p24.2, might have a role in the development of ST. In this review we are trying to delineate the most important loci involved in testicular germ tumors, the genes involved in this pathogenesis, and attempting to describe the possible mechanisms behind this tumorigenesis.