Impaired telomere length (TL) maintenance in ovarian tissue may play a pivotal role in the onset of epithelial ovarian cancer (OvC). TL in either target or surrogate tissue (blood) is currently being investigated for use as a predictor in anti-OvC therapy or as a biomarker of the disease progression, respectively. There is currently an urgent need for an appropriate approach to chemotherapy response prediction. We performed a monochrome multiplex qPCR measurement of TL in peripheral blood leukocytes (PBL) and tumor tissues of 209 OvC patients. The methylation status and gene expression of the shelterin complex and telomerase catalytic subunit (hTERT) were determined within tumor tissues by High-Throughput DNA methylation profiling and RNA sequencing (RNA-Seq) analysis, respectively. The patients sensitive to cancer treatment (n = 46) had shorter telomeres in PBL compared to treatment-resistant patients (n = 93; P = 0.037). In the patients with a different therapy response, transcriptomic analysis showed alterations in the peroxisome proliferator-activated receptor (PPAR) signaling pathway (q = 0.001). Moreover, tumor TL shorter than the median corresponded to better overall survival (OS) (P = 0.006). TPP1 gene expression was positively associated with TL in tumor tissue (P = 0.026). TL measured in PBL could serve as a marker of platinum therapy response in OvC patients. Additionally, TL determined in tumor tissue provides information on OvC patients' OS.

• Keywords
• Ovarian cancer, Shelterin, Telomerase, Telomere length, Therapy response,
• Publication type
• Journal Article MeSH

The MRE11, RAD50, and NBN genes encode for the nuclear MRN protein complex, which senses the DNA double strand breaks and initiates the DNA repair. The MRN complex also participates in the activation of ATM kinase, which coordinates DNA repair with the p53-dependent cell cycle checkpoint arrest. Carriers of homozygous germline pathogenic variants in the MRN complex genes or compound heterozygotes develop phenotypically distinct rare autosomal recessive syndromes characterized by chromosomal instability and neurological symptoms. Heterozygous germline alterations in the MRN complex genes have been associated with a poorly-specified predisposition to various cancer types. Somatic alterations in the MRN complex genes may represent valuable predictive and prognostic biomarkers in cancer patients. MRN complex genes have been targeted in several next-generation sequencing panels for cancer and neurological disorders, but interpretation of the identified alterations is challenging due to the complexity of MRN complex function in the DNA damage response. In this review, we outline the structural characteristics of the MRE11, RAD50 and NBN proteins, the assembly and functions of the MRN complex from the perspective of clinical interpretation of germline and somatic alterations in the MRE11, RAD50 and NBN genes.

• Keywords
• ATLD, DNA repair, MRE11, NBN, NBS, NBSLD, NGS, RAD50, TP53, hereditary cancer syndromes, variant interpretation,
• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   metabolism   MeSH
• DNA-Binding Proteins genetics   metabolism   MeSH
• DNA Repair Enzymes genetics   metabolism   MeSH
• MRE11 Homologue Protein genetics   metabolism   MeSH
• Acid Anhydride Hydrolases genetics   metabolism   MeSH
• Nuclear Proteins genetics   metabolism   MeSH
• Humans MeSH
• Tumor Suppressor Proteins * genetics   MeSH
• DNA Repair genetics   MeSH
• Cell Cycle Proteins * metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Ataxia Telangiectasia Mutated Proteins MeSH
• DNA-Binding Proteins MeSH
• DNA Repair Enzymes MeSH
• MRE11 Homologue Protein MeSH
• Acid Anhydride Hydrolases MeSH
• Nuclear Proteins MeSH
• Tumor Suppressor Proteins * MeSH
• NBN protein, human MeSH Browser
• Cell Cycle Proteins * MeSH
• RAD50 protein, human MeSH Browser