title: A nonsense mutation in the Xeroderma pigmentosum complementation group F (XPF) gene is associated with gastric carcinogenesis.
abstract: XPF/ERCC1 endonuclease is required for DNA lesion repair. To assess effects of a C2169A nonsense mutation in XPF at position 2169 in gastric cancer tissues and cell lines, genomic DNA was extracted from blood samples of 488 cancer patients and 64 gastric tumors. The mutation was mapped using a TaqMan MGB probe. In addition, gastric cancer cell lines were transfected with mutated XPF to explore XPF/ERCC1 interaction, XPF degradation, and DNA repair by a comet assay. The C2169A mutation was not detected in 488 samples of blood genomic DNA, yet was found in 32 of 64 gastric cancer tissue samples (50.0%), resulting in a 194C-terminal amino acid loss in XPF protein and lower expression. Laser micro-dissection confirmed that this point mutation was not present in surrounding normal tissues from the same patients. The truncated form of XPF (tXPF) impaired interaction with ERCC1, was rapidly degraded via ubiquitination, and resulted in reduced DNA repair. In gastric cancers, the mutation was monoallelic, indicating that XPF is a haplo-insufficient DNA repair gene. As the C2169A mutation is closely associated with gastric carcinogenesis in the Chinese population, our findings shine light on it as a therapeutic target for early diagnosis and treatment of gastric cancer.
authors.affiliation: Pathology Center, Shanghai First People's Hospital / Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Zhong-Hua
authors.initials: ZH
authors.lastname: Wei
authors.affiliation: Pathology Center, Shanghai First People's Hospital / Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Wen-Huan
authors.initials: WH
authors.lastname: Guo
authors.affiliation: Pathology Center, Shanghai First People's Hospital / Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Pathology Center, Shanghai First People's Hospital / Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China.
authors.forename: Wen-Hao
authors.initials: WH
authors.lastname: Suo
authors.affiliation: Pathology Center, Shanghai First People's Hospital / Faculty of Basic Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China. Electronic address: fuguhu@263.net.
authors.forename: Guo-Hui
authors.initials: GH
authors.lastname: Fu
mesh_terms: D044466:Asian People / Q000235:genetics; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D004268:DNA-Binding Proteins; D025801:Ubiquitin; C095888:xeroderma pigmentosum group F protein; C071447:ERCC1 protein, human; D004720:Endonucleases
keywords: BER; ERCC1; Gastric cancer; MMR; MTHFR; Mutation; NER; SNP; Ubiquitination; XPF; Xeroderma pigmentosum complementation group F; base excision repair; excision repair cross-complimentary group 1; methylenetetrahydrofolate reductase; mismatch repair; nucleotide excision repair; single nucleotide polymorphism