Khan, S.A.; Taylor-Robinson, S.D.; Carmichael, P.L.; Habib, N.; Lemoine, N.; Thomas, H.C.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA32
Academic Journal
Background: Cholangiocarcinoma (CCa) may arise from cholangiocyte DNA damage due to genotoxic compounds in bile. We have previously shown that human biliary tissue is exposed to genotoxic agents, as evidenced by the presence of DNA adducts. The correlation of DNA lesions along a target gene with a known "mutational signature" induced by an environmental carcinogen is a means of linking cause and effect in human cancer. The tumour suppressor gene p53 is known to have 'hotspots' for particular chemical carcinogens. Previous studies of p53 mutation in CCa have focused on exons 5-8, potentially missing gene alterations at other sites. This study examined the link between environmental carcinogens and CCa, by analysing CCa DNA for complete p53 mutational signatures. Methods: Entire p53 cDNA (all exons) from 31 intrahepatic CCa patients were screened by single strand conformational polymorphism. Exons exhibiting aberrant bands were fully sequenced. Mutations were compared to known p53 mutations in CCa, and to mutations induced by environmental mutagens, as described in p53 databases. Results and Conclusions: Five non-silent p53 mutations were found, including an exon 5 missense and a nonsense mutation, both previously reported. Three frameshifis (2 deletions and 1 insertion) in exons 4, 5, and 6, and two intron mutations were discovered, none of which have been previously reported. No predominant mutational signature was seen. This may be due to host or environmental differences in study populations, lack of data outside exons 5-8, bias in mutation reporting or because non-coding regions or other genes are involved. Further epidemiological and molecular studies are required to establish risk factors and elucidate genotoxic and host mechanisms in cholangiocarcinoma.


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