THE CYTOGENETIC THEORY OF THE PATHOGENESIS OF HUMAN ADULT MALE GERM-CELL TUMORS - REVIEW ARTICLE

Human male germ cell tumors (GCTs) represent a biological paradox beca use, in order to develop into a pluripotential tumor, a germ cell dest ined to a path of limited or no proliferation must acquire the potenti al for unlimited proliferation. In addition, it must acquire the abili ty to elicit embryonal differentiation patterns without the reciprocal inputs from fertilization and the imprinting-associated genomic chang es which are a part of normal embryonal development. Although much spe culated about, the genetic mechanisms underlying these properties of m ale GCTs remain enigmatic. Recent cytogenetic and molecular genetic an alyses of these tumors are providing new insights and new testable hyp otheses. Based on our recent work, we propose two such hypotheses. One relates to the mechanism of germ cell transformation and germ cell tu mor development. We suggest that the invariable 12p amplification note d as early as in carcinoma in situ/intratubular germ cell neoplasia (C IS/ITGCN) lesions leads to deregulated overexpression of cyclin D2, a cell cycle G1/S checkpoint regulator with oncogeneic potential. Such o verexpression reinitiates the cell cycle. We visualize this happening during the pachytene stage of meiosis through aberrant recombinational events which lead to 12p amplification. The other hypothesis relates to the origin of primary extragonadal GCTs. By comparing cytogenetic c hanges in primary mediastinal versus gonadal lesions, we propose that, in contrast to long-standing speculation that primary extra-gonadal t umors arise from embryonally misplaced primordial germ cells, these le sions arise from migration of transformed gonadal germ cells.