Etiologic Factors in Testicular Germ-Cell Tumors

Abstract

Globally, testicular cancer incidence is highest among men of northern European ancestry and lowest among men of Asian and African descent. Incidence rates have been increasing around the world for at least 50 years, but mortality rates, at least in developed countries, have been declining. While reasons for the decreases in mortality are related to improvements in therapeutic regimes introduced in the late 1970s, reasons for the increase in incidence are less well understood. An accumulating body of evidence suggests, however, that testicular cancer arises in fetal life. Perinatal factors, including exposure to endocrine disrupting chemicals, have been suggested to be related to risk. Keywords testicular germ cell tumor; seminoma; nonseminoma; perinatal etiologyAlthough a rare cancer in the general population, testicular cancer is the most common malignancy among young men in many countries. Approximately 98% of testicular cancers are germ cell tumors (TGCT). The remaining 2% include stromal tumors such as Leydig cell (~0.2%) and Sertoli cell tumors (~0.1%), as well as other more rare or poorly defined histologic types. Among TGCTs, approximately 55% are classic seminomas, 44% are nonseminomas (embryonal carcinomas, teratomas, yolk sac tumors, choriocarcinomas) and 1% are spermatocytic seminomas.

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

“…TE, YST, and choriocarcinoma are considered to be differentiated derivatives of the pluripotent progenitor, EC. TGCTs' association with developmental gonadal defects supports the prevailing model by which they originate from a multipotent stem cell arising in the germline, which fails to disable pluripotency to mature into a spermatogonium (McGlynn and Cook 2009;Sheikine et al 2012). On the other hand, recent studies identifying reversion to pluripotency in the germline (Nettersheim et al 2015;Oliveros-Etter et al 2015) question whether TGCTs entail a continuation of, versus reversion to, functional pluripotency.…”

Revisiting DNA damage repair, p53-mediated apoptosis and cisplatin sensitivity in germ cell tumors

“…The incidence of TGCTs is highly variable depending on the country, with Scandinavian countries displaying the highest incidence at nearly 10 per 100,000 whereas rates in Asian and African countries are less than 2 per 100,000 (McGlynn and Cook, 2009). However, the worldwide incidence of TGCTs has more than doubled over the past 40 years, and it is still increasing.…”

“…The risk of developing TGCT for patients with cryptorchidism approximates 10% and approximately 10% of TGCT cases are also accounted for by men with a history of cryptorchidism (Kanto et al, 2004, Prener et al, 1996. Infertility (Lilford et al, 1994) and other forms of gonadal dysgenesis constitute additional risk factors for TGCTs (McGlynn and Cook, 2009). Prior diagnosis of TGCT also predisposes to development of a second TGCT in the contralateral testis.…”

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

“…Individually and collectively, however, these susceptibility genes account for only a modest portion of inherited risk. Many genes and inherited factors remain to be discovered, their functions in normal development characterized, and the ways that dysfunction leads to TGCTs investigated (16,17).Risk for TGCTs is strongly associated with various testicular abnormalities (TAs) such as undescended testis (cryptorchism) and testicular atrophy (18)(19)(20)(21)(22)(23). This association, sometimes referred to as "testicular dysgenesis syndrome," suggests shared genetic and environmental origins for TGCTs and abnormalities in urogenital development (24)(25)(26).…”