Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults

Abstract

Testicular germ cell tumors (TGCTs) of adults and adolescents are thought to be derived from primordial germ cells or gonocytes. TGCTs develop postpuberty from precursor lesions known as intratubular germ cell neoplasia undifferentiated. The tumors can be divided into two groups based on their histology and clinical behavior; seminomas resemble primordial germ cells or gonocytes and nonseminomas resemble embryonic or extraembryonic tissues at various stages of differentiation. The most undifferentiated form of nonseminoma, embryonal carcinoma, resembles embryonic stem cells in terms of morphology and expression profiling, both mRNAs and microRNAs. Evidence supports both environmental factors and genetic predisposition underlying the development of TGCTs. Various models of development have been proposed and are discussed. In TGCTs, gain of material from the short arm of chromosome 12 is invariable: genes from this region include the proto-oncogene KRAS, which has activating mutations in approximately 10% of tumors or is frequently overexpressed. A number of different approaches to increase the understanding of the development and progression of TGCTs have highlighted the involvement of KIT, RAS/RAF/MAPK, STAT, and PI3K/AKT signaling. We review the role of these signaling pathways in this process and the potential influence of environmental factors in the development of TGCTs.

Minimum regions of genomic imbalance in stage I testicular embryonal carcinoma and association of 22q loss with relapse

“…Gain of RASGEF1A at 10q11.21 and increased expression relative to normal testes suggests a further mechanism by which TGCTs can activate RAS signaling, known to be important in TGCT (McIntyre et al, 2008). KRAS is contained in the pathognomic region of gain on chromosome arm 12p and is highly expressed or mutated in TGCT (McIntyre, et al, 2005b).…”

“…Previous data including genomic changes highlights the importance of RAS and PI3 kinase signaling in TGCT (McIntyre et al, 2008). Gain and mutation of KIT has been described in SE (McIntyre et al, 2005a) where overexpression is ubiquitous and also seen in approximately 30% of NS.…”

Risk of metachronous contralateral testicular germ cell tumors: A population‐based study of 7,102 Norwegian patients (1953–2007)

“…21,22 TIN is the progenitor of TGCT, and more than Epidemiology 50% of all patients with TIN will develop an invasive TGCT during a 5-year period if left untreated. 23,24 Approximately 5% of patients with unilateral TGCT have TIN in the contralateral testis, which corresponds well to the reported incidence of bilateral TGCT.…”

“…21,24,32 A prediction of this notion is that the incidence rate of a second TGCT would rise at the same speed as the first one, given that both testicles share the same genetic predisposition and are exposed to the same environment. Our observation, that the relative risk (SIR) of developing a second TGCT for patients with unilateral TGCT compared to the general population was the same (about 16) in both periods, is in accordance with this notion.…”

In vitro study on shRNA-mediated reduction of testis developmental related gene 1 expression and its effects on the proliferation, invasion and apoptosis of NTERA-2 cells

“…TGCT treatment is associated with chronic side effects; patients with advanced-stage cancer are less sensitive to comprehensive treatments, resulting in a poor prognosis (5). The molecular biology of TGCT remains largely unknown, but the onset and development of the disease is a process that involves multiple genes (6). Increased understanding of the molecular biology of TGCT is essential in order to define targeted treatments and identify novel markers for diagnosis and prognosis.…”