P-704 Genomic DNA damage in individuals with sex determination defects and germ cell cancer

Abstract Study question Does genomic instability contribute to common mechanisms underlying variable defects of gonadal differentiation and susceptibility germ cells cancer? Summary answer Genomic DNA damage associated phenotypes in leukocytes tissue indicate systemic dependence on repair mechanisms, connected cell tumorigenesis when defective. What is known already Variabilities related dysfunctional sex chromosomes are Differences Sex Development (DSD), characterized by dysgenic gonads, deregulated gender specification failed maturation. This causes infertility elevated risk tumors (GCT). DSD was described individuals with Swyer syndrome (46,XY, females), complete or partial androgen insensitivity (CAIS, PAIS, 46,XY, Turner (45,X0, females) Klinefelter (47,XXY, males) syndromes, malignant tumor development. Unbalanced karyotype genome-wide changes, including proliferation delay, proteostasis, activation innate immune response, that genome phenotypes. design, size, duration Individuals were enrolled into study during routine examination our clinic. Samples from men testicular (TGCT) used as positive controls for malignancy. The samples collected written patients’ informed consent. For this we analyzed 40 19 GCT. Control group contained fertile women appropriate age interval. Participants/materials, setting, methods groups included (n = 7), 11), 6), CAIS 9) syndromes TGCT 14). Blood EDTA DNA, RNA protein isolated leukocytes. CAIS, underwent gonadectomy, formed additional histologically proven GCT (DSD-GCT, n 6). quantitative real-time PCR (qRT-PCR), immunoblotting, mass spectrometry, immunofluorescence. Main results the role chance We an increase compared unaffected via γH2AX, labeling double strand brakes (immunoblotting: p 0,0438; DSD-GCT 0,0185; NS; 0,0117; 0,0068; 0,0207) gonads (immunofluorescence, γH2AX+ puncta per cell: 75, < 0,0001; 46, 33, 40, 0,0001, n-number analyzed). malignancy evaluating response IFNβ ISG15 levels (DSD-GCT 0,0350 0,0411; 0,0007 0,0437) inhibition autophagy decrease LC3 accumulation P62 proteins 0,0001 0,0453; 0,036 0,0219). supported whole proteome analysis. Compromised integrity suggested involvement pathways, illustrated upregulation deltaTP53 (Swyer 0,0104; 0,0478; 0,0046; 0,0426; 0,006). TP53 exhibited significant missense mutations sequences, encoding transactivation domains, which compromised stability, particularly, also restore upon direct Enoxacin (p 0,0056) Bafilomycin A1 0,0034). T test statistical Limitations, reasons caution based a limited number available rare genetic some observed only 1 out 10,000 clinical cases. Therefore, development vitro models will promote research area. Wider implications findings elucidated possibilities prophylactic treatments DSD-individuals well new diagnostic approaches It additionally emphasized importance address research. Trial registration NA