Functional deficiency of the FEN1 gene has been suggested to cause genomic instability and cancer predisposition. We have identified a group of FEN1 mutations in human cancer specimens. Most of these mutations abrogated two of three nuclease activities of flap endonuclease 1 (FEN1). To demonstrate the etiological significance of these somatic mutations, we inbred a mouse line harboring the E160D mutation representing mutations identified in human cancers. Selective elimination of nuclease activities led to frequent spontaneous mutations and accumulation of incompletely digested DNA fragments in apoptotic cells. The mutant mice were predisposed to autoimmunity, chronic inflammation and cancers. The mutator phenotype results in the initiation of cancer, whereas chronic inflammation promotes the cancer progression. The current work exemplifies the approach of studying the mechanisms of individual polymorphisms and somatic mutations in cancer development, and may serve as a reference in developing new therapeutic regimens through the suppression of inflammatory responses.
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We acknowledge G. Pfeifer, M. Lieber, W. Chen, K. Justus, L.D. Finger and S. Alas for their critical review of the manuscript. We thank R. Kolodner (University of California, San Diego) for kindly providing yeast strains, D. Zeng (City of Hope) for providing serum standard of antibodies to nuclear antigens and dsDNA, and the City of Hope DNA sequencing core facility for DNA sequencing analyses. This work was supported by a US National Institutes of Health grant R01CA073764 to B.H.S. and by the lung cancer program of City of Hope's Comprehensive Cancer Center.
The authors declare no competing financial interests.
FEN1 mutation detection in human cancers. (PDF 30 kb)
Knock-in of E160D Fen1 mutant in mouse germline. (PDF 163 kb)
E160D mice develop subcutaneous inflammation, lymphoproliferative disorder, and extramedular hematopoiesis. (PDF 156 kb)
Analysis for loss of heterozygosity of lung tumors in heterozygous E160D mice. (PDF 98 kb)
FEN1 mutations identified in 12 major human cancers. (PDF 18 kb)
Cytokine profiles of WT normal and E160D inflammatory and adenoma lung tissues. (PDF 31 kb)
Oligonucleotide sequences and their applications in this study. (PDF 37 kb)
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Zheng, L., Dai, H., Zhou, M. et al. Fen1 mutations result in autoimmunity, chronic inflammation and cancers. Nat Med 13, 812–819 (2007). https://doi.org/10.1038/nm1599
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