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Published on: July 28, 2010
MRE11 Deficiency Occurs in a Small Group of Cancers from Various Different Tumor Entities
Viktor Reiswich1, Henry Recksiek1, Katharina Möller1
1Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Abstract:
Background/Objectives: The double-strand break repair protein MRE11 forms the core of the MRE11/RAD50/NBS1 (MRN) complex. Cancers with reduced MRE11 expression have been suggested to be more sensitive to radio-chemotherapy and may be subject to synthetic lethality. The aim of this study was to assess the prevalence of MRE11 deficiency and the potential role and clinical significance of elevated and/or reduced MRE11 expression in human cancer. Methods: A tissue microarray containing 14,966 samples from 134 different tumor entities was analyzed for MRE11 by immunohistochemistry. Results: In normal tissues, strong nuclear MRE11 staining occurred in almost all cell types. In cancers, nuclear MRE11 staining was strong in 11,797 (91.0%), moderate in 1018 (7.9%), weak in 86 (0.7%), and completely absent (MRE11 deficiency) in 55 (0.4%) of 12,956 informative tumor samples. Only six tumor entities had more than one MRE11-deficient cases including hepatocellular carcinoma (9 of 193), intestinal type gastric adenocarcinoma (4 of 208), endometrioid endometrial carcinoma (5 of 268), pulmonary adenocarcinoma (2 of 165), colorectal adenocarcinoma (CRC, 16 of 2183), and clear cell renal cell carcinoma (ccRCC, 7 of 1011). Reduced MRE11 staining was associated with mismatch repair deficiency (dMMR) in CRC and in gastric adenocarcinoma (p < 0.0001 each), 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). Conclusions: MRE11 is highly expressed in most cancers. Reduced MRE11 expression is associated with aggressive phenotype in multiple cancer types. The potential to exploit MRE11 deficiency as a target for synthetic lethality deserves to be further explored.
Insights
MRE11 protein deficiency is rare in most cancers but linked to aggressive disease in several types. Further research into MRE11 deficiency as a synthetic lethality target is warranted.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MRE11 protein is crucial for DNA double-strand break repair as part of the MRE11/RAD50/NBS1 complex.
- Reduced MRE11 expression in cancers suggests potential sensitivity to radio-chemotherapy and synthetic lethality approaches.
Purpose of the Study:
- To determine the prevalence of MRE11 deficiency across various human cancers.
- To investigate the clinical significance of MRE11 expression levels (elevated or reduced) in cancer.
Main Methods:
- Immunohistochemistry was used to analyze MRE11 expression in a large tissue microarray (14,966 samples, 134 tumor types).
- Statistical analyses correlated MRE11 expression with clinicopathological features and other biomarkers like mismatch repair deficiency.
Main Results:
- MRE11 deficiency was rare (0.4%) but observed in specific tumor types like colorectal and clear cell renal cell carcinoma.
- Reduced MRE11 expression correlated with aggressive features, including advanced stage, high grade, and mismatch repair deficiency in several cancers.
Conclusions:
- MRE11 is highly expressed in the majority of human cancers.
- Decreased MRE11 expression is associated with a more aggressive cancer phenotype.
- MRE11 deficiency presents a potential therapeutic target for synthetic lethality strategies.
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