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The naked mole rat (NMR, Heterocephalus glaber) is a long-lived underground mammal, whose maximum lifespan can be up to 30 years and more than 7 times longer than house mouse. In addition, they are resistant to both spontaneous and experimentally induced tumorigenesis. These special biologic or behavioral characteristics make them most suitable for cancer and longevity research. The recent genome sequencing of NMR has provided the opportunity for the study of molecular mechanisms of such extreme traits. In this study, we carried out a comparative analysis of the complete set of NMR and rat genes. First, we identified all orthologous genes shared between these two animals. We further focused on the rat genes that were absent in NMR and used KEGG pathway database to identify the biological meaning of their proteins. The top three pathways include “Cytokine-cytokine receptor interaction”, “Neuroactive ligand-receptor interaction” and “Pathways in cancer”, which was consistent with the unique NMR traits. Interestingly, in the rat cancer pathway which contains 13 paths leading to evading apoptosis, 8 of them appeared to be interrupted in NMR. Finally, we found that 50% of genes lacked in “Pathways in cancer” and 40% of genes lacked in “MAPK signaling pathway” have been known to be related to a variety of cancers. Overall, this study provides insights into searching for new cancer-related genes and understanding the anti-cancer mechanism of NMR.