The ability to transmit genetic information through generations depends on preservation of genome integrity. Genetic abnormalities affect cell differentiation, causing tissue specification defects and cancer. We addressed genomic instability in individuals with Differences of Sex Development (DSD), characterized by gonadal dysgenesis, sex reversal, infertility, high susceptibility for different types of cancer, especially Germ Cell Tumors (GCT), and in men with testicular GCTs. We analyzed the whole proteome of leukocytes and confirmed it with immunoblotting and quantitative PCR analysis. Additional data from tissue biopsies strengthen our observations in peripheral blood. In particular, the analysis of leukocytes and dysgenic gonads uncovered DNA damage phenotypes, supported by changes in DNA damage response mechanisms: altered autophagy and innate immune response, suppressed TP53-dependent DNA repair.