Genetic changes associated with testicular cancer susceptibility

Abstract

Testicular germ cell tumor (TGCT) is a highly heritable cancer primarily affecting young white men. Genome-wide association studies (GWAS) have been particularly effective in identifying multiple common variants with strong contribution to TGCT risk. These loci identified through association studies have implicated multiple genes as associated with TGCT predisposition, many of which are unique among cancer types, and regulate processes such as pluripotency, sex specification, and microtubule assembly. Together these biologically plausible genes converge on pathways involved in male germ cell development and maturation, and suggest that perturbation of them confers susceptibility to TGCT, as a developmental defect of germ cell differentiation.

Keywords: Germ cell tumor; Sex development; Testicular cancer.

Figure 1

TGCT pathogenesis in relation to germ cell development. The stages of germ cell development are shown above in red. Normal germ cell development stages are shown in green, and aberrant TGCT precursors are shown with blue. PGC=primordial germ cell. GCNIS=germ cell neoplasia in situ.

Figure 2

Sex Determination Signaling. GWAS hits for TGCT predisposition are in red, other components in blue. Most components linking the initially bipotential gonad to DMRT1 and other downstream effectors are transcription factors. Exceptions include HPGDS, required for translocation of SOX9 into the nucleus, and the ligand/receptor pair PGD2 and TFDP2. TIPARP is not included, which influences the overall hormonal milieu.