Introduction Patients with differences of sex development (DSD) are characterized by gonadal dysgenesis, infertility and high susceptibility to germ cell tumors (GCT). Genomic instability can lead to cell death or malignancy. Here, we aim to investigate the cause for GCT by estimating telomere length for characterization the grade of DNA damage and autophagy, the only one DNA damage response (DDR) mechanism known so far to regulate telomere crisis.
Methods We measured telomeres length in peripheral blood leukocytes of 109 DSD-patients diagnosed with Swyer (n=16), Turner (n=56), Complete Androgene Insensitivity (CAIS) (n=17), Mixed-Gonadal Dysgenesis (MGD) (n=11) or Klinefelter (n=9) syndromes vs. 11 healthy fertile controls, using the RHTLQ kit. We also treated lymphoblastoid cell lines (3xTurner, 1xSwyer, 4xControl) with the autophagy inhibitor bafilomycin, to examine its role in telomere homeostasis.
Results We observed a significantly increased telomere length in Swyer, Turner and MGD patients’ groups with high DNA damage, while those with GCT showed a decrease. This indicates a stimulated DDR for these patients’ groups, which is compromised in blood samples of patients with gonadal GCT. Moreover, patients with the most severe genome damage (e.g. structural damage of X chromosome, n=22) had significantly shorter telomeres than healthy controls. We also observed telomere elongation in cell culture upon autophagy inhibition.
Conclusion The telomere length reversely correlates with the severity of genome damage of the cell, unless DDR is activated in DSD-patients. Autophagy inhibition supports telomeres DDR and, therefore, elongation. This knowledge will facilitate early GCT diagnosis and reduce practice of prophylactic gonadectomy.
