From gonocytes to testicular cancer: the role of impaired gonadal development.

Testicular germ-cell tumors occur primarily in young individuals, and the tumors in this age group (seminomas or nonseminomas) are derived from a preinvasive precursor cell called carcinoma in situ (CIS) or intratubular germ-cell neoplasia. These tumors have been a growing problem, especially in highly developed industrialized countries. A hypothesis was put forward that CIS originates from arrested fetal germ cells, thus testicular cancer is a developmental disease of germ-cell differentiation. This notion was supported by comparative studies of the gene expression at the protein and RNA level, which demonstrated a close similarity of CIS to primordial germ cells and gonocytes with many features of embryonic stem cells. The arrest of germ-cell differentiation is thus the key first event, which may be followed by malignant transformation and overt germ-cell cancer in young adult age, usually after puberty. In most cases the arrest/delay of germ-cell differentiation is caused by testicular dysgenesis, a multifactorial and complex syndrome that has a broad spectrum of phenotypes ranging from moderate impairment of spermatogenesis to severe disorders of sexual development and differentiation. The most severe cases are a result of inherited genetic aberrations, but the etiology of the common sporadic testicular cancer must involve environmental factors, including maternal lifestyle and possibly an early exposure to endocrine disruptors. The effects of environmental factors are likely modulated by genomic variation (polymorphisms), thus explaining the individual susceptibility and population-level differences in the incidence of testicular cancer.