Genetics and biology of adult human male germ cell tumors.

TLDR

Adult human male germ cell tumors uniquely model the transformation of totipotent germ cells into pluripotent tumor cells, exhibiting diverse differentiation phenotypes and remarkable cisplatin sensitivity, yet their molecular mechanisms remain poorly understood. This review aims to discuss recent insights into germ cell tumor biology and to propose novel testable genetic models. The authors analyze recent studies of cyclin D2 overexpression, differentiation pathways, and p53‑dependent apoptosis to develop these models. Recent findings indicate that cyclin D2 overexpression is an early oncogenic event, differentiation is governed by multiple interacting pathways—including loss of totipotency regulators and imprinting—and chemotherapy sensitivity or resistance may involve p53‑dependent apoptotic mechanisms.

Abstract

Adult human male germ cell tumors (GCTs) provide a unique opportunity to study the generation of a transformed pluripotential cell from a totipotential GC in lineage differentiation and on the path to gametogenesis. The pluripotentiality of the tumor cells manifests as histological differentiation into GC-like undifferentiated (SE), primitive zygotic (EC), embryonal-like somatically differentiated (TE), and extra-embryonally differentiated (CC, YST) phenotypes. The tumors and cell lines derived from them comprise exceptional model systems for the molecular analysis of human embryonal cell fate and lineage differentiation. The majority of GCTs show exquisite sensitivity to cisplatin-based treatment and have served as models for the development of chemotherapy for solid tumors. Until recently, the molecular mechanisms of GC transformation, GCT differentiation, or GCT chemotherapy sensitivity and resistance were understood poorly. Very recent studies of GCTs have suggested that: (a) overexpression of cyclin D2 is a very early, possibly the oncogenic, event in GC tumorigenesis; (b) differentiation in GCTs may be governed by several possibly interacting pathways, such as loss of regulators of GC totipotentiality and of embryonic development, and genomic imprinting; and (c) chemotherapy sensitivity and resistance may be rooted in part in a p53-dependent apoptotic pathway. In this review, these new data are discussed in the context of GC and GCT biology, and several novel testable genetic models are proposed.