Genetics and biology of adult human male germ cell tumors

Adult human male germ cell tumors (GCTs) provide a unique opportunity to st udy the generation of a transformed pluripotential cell from a totipotentia l GC in lineage differentiation and on the path to gametogenesis. The pluri potentiality of the tumor cells manifests as histological differentiation i nto GC-like undifferentiated (SE), primitive zygotic (EC), embryonal-like s omatically differentiated (TE), and extra-embryonally differentiated (CC, Y ST) phenotypes. The tumors and cell lines derived from them comprise except ional model systems for the molecular analysis of human embryonal cell fate and lineage differentiation. The majority of GCTs show exquisite sensitivi ty to cisplatin-based treatment and have served as models for the developme nt of chemotherapy for solid tumors. Until recently, the molecular mechanis ms of GC transformation, GCT differentiation, or GCT chemotherapy sensitivi ty and resistance were understood poorly. Very recent studies of GCTs have suggested that: (a) overexpression of cyclin D2 is a very early, possibly t he oncogenic, event in GC tumorigenesis; (b) differentiation in GCTs may be governed by several possibly interacting pathways, such as loss of regulat ors of GC totipotentiality and of embryonic development, and genomic imprin ting; and (c) chemotherapy sensitivity and resistance may be rooted in part in a p53-dependent apoptotic pathway, In this review, these new data are d iscussed in the context of GC and GCT biology, and several novel testable g enetic models are proposed.