MRE11 deficiency occurs in a small group of cancers from various different tumor entities

The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. The MRN complex acts as an early DNA damage response element which is involved in different repair pathways including homologous recombination (HR), non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) repair. In cancers, altered MRE11 expression has been described in various tumor entities (e.g. carcinoma of the prostate, colon and stomach) and both up- and downregulation was associated with adverse tumor features. Most of the clinical interest comes from studies highlighting the predictive role of MRE11 expression. MRE11 overexpressing cancers have been described to be more radioresistant while low-expressors were more sensitive to radiation and chemotherapy with camptothecin and gemcitabine. Several MRE11 inhibitors are currently being investigated in clinical trials as radiosensitizers. To better understand the role of MRE11 expression in cancer, a tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed. In normal tissues, a strong nuclear MRE11 staining occurred in almost all cell types. Most cancers had a nuclear MRE11 staining that was strong in 11,797 (91.0%), moderate in 1,018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4 %) of the 12,956 informative tumor samples. More than one case of MRE11 deficiency was only seen in 6 tumor entities including hepatocellular carcinoma (10 of 292; 3.4%), gastric adenocarcinoma, intestinal type (4 of 208; 1.9%), endometrioid endometrial carcinoma (5 of 268; 1.9%),pulmonary adenocarcinoma (2 of 165; 1.2%), colorectal adenocarcinoma (CRC, 16 of 2,183; 0.7%), and clear cell renal cell carcinoma (ccRCC, 7 of 1,011; 0.7%). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC (p<0.0001 each) and in gastric adenocarcinoma (p<0.0001), advanced pT stage (p=0.0003) and L1 status (p=0.0019) in testicular seminoma, high grade (p<0.05), advanced pT (p<0.0001), and high UICC stage (p=0.0014) in ccRCC, advanced pT stage in high-grade serous ovarian carcinoma (p=0.0396), and nodal metastases in papillary thyroid cancer (p=0.0332). High MRE11 expression was linked to nodal metastasis in hepatocellular carcinoma (p=0.0258). It is concluded that MRE11 is highly expressed in most cancers and its reduced expression is associated with an aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored.