title: Analysis of p53 mutations for a mutational signature in human intrahepatic cholangiocarcinoma.
abstract: Cholangiocarcinoma development may be related to cholangiocyte DNA damage from 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. Establishing the presence of a 'mutational signature' in tumour suppressor genes from tumour tissue provides a means of linking cause and effect in human cancer. Inactivation of p53, known to have 'hot-spots' for particular chemical carcinogens, has previously been linked to human cholangiocarcinoma. However, previous p53 studies have focused on exons 5-8, potentially missing gene alterations at other sites. This study examined the putative link between environmental carcinogens and intrahepatic cholangiocarcinoma by analysing DNA from 31 patients for complete p53 mutational signatures, using single strand conformational polymorphism and polymerase chain reaction. All mutations found were compared to known p53 mutations in cholangiocarcinoma and to mutations induced by environmental mutagens, as described in p53 databases. Five non-silent p53 mutations were found, including three new frameshift mutations and two new intron mutations which have not previously been reported in cholangiocarcinoma. Two frameshifts were due to deletions and the third due to an insertion in exon 5. There was no predominant mutational spectrum amongst the set of cholangiocarcinoma samples studied, or on combining these mutations with the dataset of known p53 mutations in cholangiocarcinoma. Several reasons may explain this, including lack of data outside exons 5-8, bias in mutation reporting, the involvement of mutations in non-coding regions or genes other than p53, or the possibility that there is no carcinogenic specific agent and therefore no signature.
authors.affiliation: Liver Unit, Department of Medicine A, 10th Floor, QEQM Wing, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK. shahid.khan@imperial.ac.uk
authors.forename: Shahid A
authors.initials: SA
authors.lastname: Khan
authors.forename: Simon D
authors.initials: SD
authors.lastname: Taylor-Robinson
authors.forename: Paul L
authors.initials: PL
authors.lastname: Carmichael
authors.forename: Nagy
authors.initials: N
authors.lastname: Habib
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Howard C
authors.initials: HC
authors.lastname: Thomas
mesh_terms: D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics*; D001653:Bile Ducts, Intrahepatic; D002273:Carcinogens / Q000494:pharmacology; D018281:Cholangiocarcinoma / Q000235:genetics*; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D016158:Genes, p53 / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D002273:Carcinogens; D003062:Codon; D012333:RNA, Messenger